KR20210137442A - How to treat or prevent heart failure and reduce the risk of heart failure - Google Patents

Abstract

The present invention is directed to treating or preventing congestive heart failure, ventricular systolic insufficiency, ventricular diastolic insufficiency or ejection fraction-preserving heart failure and for reducing the risk of congestive heart failure, ventricular systolic insufficiency, ventricular insufficiency or ejection fraction-preserving heart failure. Useful compositions and methods are provided.

Description

How to treat or prevent heart failure and reduce the risk of heart failure

The present invention is directed to treating or preventing congestive heart failure, ventricular systolic insufficiency, ventricular diastolic insufficiency or ejection fraction-preserving heart failure and for reducing the risk of congestive heart failure, ventricular systolic insufficiency, ventricular insufficiency or ejection fraction-preserving heart failure. Useful compositions and methods are provided.

Lowering low-density lipoprotein (LDL) is an important therapeutic strategy in the management of cardiovascular disease. In fact, LDL-lowering statin drugs such as Crester, Repeater, Prabachol and Nephew are widely used and are among the most prescribed drugs. For some time, it was generally accepted that an increase in high-density lipoprotein (HDL) could be a treatment for cardiovascular disease. Several HDL-raising drugs have been developed, including niacin and CETP inhibitors such as torcetrapib, anacetrapib, evacetrapib and dalcetrapib.

Cholesterol ester transfer protein (CETP), also known as plasma lipid transfer protein, is a hydrophobic glycoprotein that is synthesized in several tissues but mainly in the liver. CETP facilitates the bidirectional transfer of cholesterol esters and triglycerides between all plasma lipoprotein particles. The first evidence for the effect of CETP activity on plasma lipoproteins was provided by observations in people with a genetic deficiency of CETP. The first CETP mutation was identified as a cause of markedly elevated HDL-C in Japan in 1989. Ten mutations associated with CETP deficiency have since been identified in Asians and one in Caucasians. In Japan, 57% of subjects with HDL-C > 100 mg/dL were found to have the CETP gene mutation. In addition, 37% of Japanese people with HDL-C levels of 75-100 mg/dL carry the CETP gene mutation. Subsequently, studies of animals treated with anti-CETP antibodies showed that CETP inhibition significantly increased the concentration of HDL-C. Consistent with these observations in CETP deficient patients and in rabbits treated with anti-CETP antibodies, it was found that treatment of humans with CETP inhibitor drugs resulted in increased concentrations of HDL cholesterol and apoA-I (the major apolipoprotein of HDL). Numerous epidemiological studies have correlated the effects of changes in CETP activity with coronary heart disease risk, including studies of human mutations (Hirano et al., Curr. Opin. Lipido . (2000) 11(4), 389-396).

Atherosclerosis, including coronary heart disease (CHD), stroke and peripheral vascular disease, and its clinical consequences represent a huge burden on the international health care system. CETP inhibitors have been under development for some time with the hope that they will be useful in the treatment or prevention of atherosclerosis. Several classes of CETP inhibitor drugs increase HDL and decrease LDL in humans and treat atherosclerosis and cardiovascular disease, including dalcetrapib, torcetrapib, anacetrapib, evacetrapib, BAY 60-5521, etc. appeared to have an effect. However, there is evidence that these drugs may not be safe and effective for all patients. Clinical trials with torcetrapib were terminated in Phase III due to the incidence of mortality in patients treated with torcetrapib plus atorvastat compared to patients treated with atorvastatin alone. Clinical trials with dalcetrapib were also discontinued in this case phase III due to lack of efficacy compared to statins alone.

The dalcetrapib mortality and morbidity trial (dal-OUTCOMES) was a double-blind, randomized, placebo-controlled, parallel group, multicenter study of stable CHD patients recently admitted for acute coronary syndrome (ACS). This study was conducted to test the hypothesis that CETP inhibition would reduce the risk of recurrence of cardiovascular events in patients with recent ACS by increasing HDL-C levels through CETP inhibition. Eligible patients participated in a single-blind placebo run-in period of approximately 4-6 weeks to allow the patient to be stable and complete the planned revascularization procedure. At the end of the run-in period, stable, eligible patients were randomized in a 1:1 ratio to either 600 mg of dalcetrapib or placebo in addition to evidence-based care for ACS. The dal-OUTCOMES study led to unexpected observations related to cardiovascular disease progression. Despite a significant increase in HDL-c, on-treatment patients did not show a significant reduction in cardiovascular events and the study was terminated.

Pharmacogenomic studies of the dal-OUTCOMES study population were conducted to study inter-individual variability in dalcetrapib response, to identify genetic markers for predicting therapeutic response to dalcetrapib or other CETP inhibitors, for patient stratification and treatment selection. carried out It was found that the effect of dalcetrapib on atherosclerotic outcome is determined by a correlated polymorphism of the adenylic acid cyclase type 9 (ADCY9) gene. Specifically, rs11647778, rs1967309, rs12595857, rs2239310, rs11647828, rs8049452, rsl2935810, rs74702385, rs17136707, rs8061182, rs111590482, rs4786454, rs4786454, rs22831971508, rsl1531999911, 12933720675 Twenty SNPs occurring in , were found to be related to the response to the CETP inhibitor dalcetrapib. In particular, rs11647778 or rsl967309 together are in strong linkage disequilibrium (r2=0.79) and are strongly associated with response to dalcetrapib. This finding was disclosed in WO2014154606A1, WO2016016157A1, Tardif et al., Circulation: Cardiovascular Genetics, (2015) 8:372-382, and Tardif et al., Circulation: Cardiovascular Genetics , (2016) 9:340-348, respectively, which is incorporated herein by reference.

Adenylate cyclases (ADCYs) catalyze the formation of cyclic adenosine-3',5'-monophosphate (cAMP), a universal secondary messenger from adenosine triphosphate (ATP). The adenylic acid cyclase family consists of 10 members (ADCY1-ADCY10) with high primary sequence similarity at the catalytic site. ADCY9 is the ninth, least characterized and widely distributed isoform of adenylic acid cyclase. Polymorphisms in the ADCY9 gene have been shown to affect individual responses to inhalation therapy in asthmatic patients. (Kim et al., J Clin Pharm Ther. (2011) 36:399-405) Recently, another ADCY9 gene polymorphism has been shown to be associated with body mass index and clinical grade of obesity. (Berndt et al., Nat Genet. (2013) 45:501-512) However, the underlying mechanisms responsible for the interaction between ADCY9 and CETP have not been previously disclosed.

There is still a need to develop novel therapeutic compositions and methods for the treatment or prevention of subjects with cardiovascular conditions.

One aspect of the invention provides a composition comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor.

Another aspect of the invention provides a method of treating or preventing congestive heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has reduced expression or activity of ADCY compared to a control level. level, wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor.

Another aspect of the invention provides a composition comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

Another aspect of the invention provides a method of reducing the risk of dilated heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has reduced expression or activity of ADCY compared to a control level. level, wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

Another aspect of the invention provides a composition comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

Another aspect of the present invention provides a method of reducing the risk of systolic heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the reduced expression or activity level of ADCY results in a decrease in the expression or activity level of ADCY in the subject when the subject is in need thereof. indicates that they will benefit from administration. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

Another aspect of the invention provides a composition comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor.

Another aspect of the invention provides a method of treating or preventing ventricular systolic insufficiency comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has reduced expression of ADCY compared to a control level. or activity level, wherein reduced expression or activity level of ADCY indicates that the subject will benefit from administration of the CETP inhibitor.

Another aspect of the invention provides a composition comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor.

Another aspect of the invention provides a method of reducing the risk of ventricular systolic insufficiency comprising administering to the subject an effective amount of a CETP inhibitor to the subject in need thereof, wherein the subject has a decrease in ADCY compared to a control level is known to have elevated expression or activity levels, wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor.

Another aspect of the invention provides a composition comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor.

Another aspect of the present invention provides a method of treating or preventing ventricular diastolic dysfunction comprising administering to a subject an effective amount of a CETP inhibitor to a subject in need thereof, wherein the subject has a decrease in ADCY compared to a control level is known to have elevated expression or activity levels, wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor.

Another aspect of the invention provides a composition comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor.

Another aspect of the invention provides a method of reducing the risk of ventricular diastolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has reduced expression of ADCY compared to a control level. or activity level, wherein reduced expression or activity level of ADCY indicates that the subject will benefit from administration of the CETP inhibitor.

Another aspect of the invention provides a method of reducing the risk of ventricular diastolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has reduced expression of ADCY compared to a control level. or activity level, wherein reduced expression or activity level of ADCY indicates that the subject will benefit from administration of the CETP inhibitor.

Another aspect of the invention provides a composition comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor.

Another aspect of the invention provides a method of treating or preventing ejection fraction-preserving heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has reduced expression of ADCY compared to a control level or activity level, wherein reduced expression or activity level of ADCY indicates that the subject will benefit from administration of the CETP inhibitor.

Another aspect of the invention provides a composition comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor.

Another aspect of the invention provides a further method of reducing the risk of heart failure with preserved ejection fraction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has a decrease in ADCY compared to a control level is known to have elevated expression or activity levels, wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor.

Included in the context of the present invention.

1A shows that Adcy9 mRNA expression in the heart (analyzed by RT-qPCR) was reduced by 50% in Adcy9 ^WT/Gt mice and at least 90% in Adcy9 ^{Gt/Gt mice compared to WT (wild-type).} 1E shows that ADCY9 protein expression was abolished in Adcy9 ^{Gt/Gt mice compared to WT in skeletal muscle.}
1B depicts plasma PCSK9 concentrations of WT and Adcy9 ^Gt/Gt mice infected with AAV8-Pcsk9 ^D377Y at baseline, 1 week post infection and before the onset of an atherosclerotic diet, 8 and 12 weeks after an atherosclerotic diet.
1C shows that PCSK9 ^D377Y induced a similar 90% reduction in hepatic LDL receptor expression in WT and Adcy9 ^{Gt/Gt .}
1D depicts plasma cholesterol levels of WT and Adcy9 ^Gt/Gt mice infected with AAV8-Pcsk9 ^D377Y at baseline, 1 week post infection and before the start of an atherosclerotic diet, 4 weeks, 8 weeks and 12 weeks after an atherosclerotic diet.
2A and 2B depict ^{chromatographic lipoprotein profiles of WT ( FIG. 2A ) and Adcy9 Gt/Gt} ( FIG. 2B ) mice at baseline and after 16 weeks of atherosclerotic diet.
3A shows 11.3±2.1% of the intimal surface covered with atherosclerotic lesions in WT mice compared to 3.8±0.6% in sacrificed Adcy9 ^{Gt/Gt mice.} Atherosclerotic lesions were quantified in whole aorta incised from the front. 3D depicts atherosclerotic lesions in the aorta of WT and Adcy9 ^Gt/Gt mice revealed by Oil Red O staining.
3B shows cross-sectional quantification of plaque area along the aortic root of WT and Adcy9 ^{Gt/Gt mice.} 3E depicts atherosclerotic lesions in aortic valve cross-sections of WT and Adcy9 ^{Gt/Gt mice.}
3C and 3F show that all WT animals had plaques in the brachial artery in contrast to Adcy9 ^{Gt/Gt mice (100%, 50% vs. P<0.05).} Plaques from WT mice were also larger and exhibited more frequent fibrin deposits (P<0.05) and cap rupture on the surface compared to Adcy9 ^{Gt/Gt mice.}
4A shows that CD68-positive foam cells, a major component of atherosclerotic plaques, represent 19.0±1.9% and 11.4±2.1% of lesion area in WT and Adcy9 ^{Gt/Gt mice, respectively (P<0.05).} 4D depicts immunofluorescence detection of CD68-positive macrophages (foam cells).
4B shows in situ hybridization analysis of Adcy9 expression in atherosclerotic lesions at the site of foam cell accumulation in WT and Adcy9 ^{Gt/Gt mice.}
4C and 4E depict immunofluorescence detection of Ki67 indicating that proliferation of CD68-positive foam cells was significantly reduced in Adcy9 ^{Gt/Gt compared to WT (P<0.05).}
Figure 5a shows that endothelium-dependent vasodilation for ACh was enhanced in untreated animals (AAV8- Pcsk9 ^D377Y and no atherosclerotic diet) in the femoral arteries of Adcy9 ^{Gt/Gt mice compared to WT;} In contrast, endothelium-independent vasodilation for nitric oxide donor SNPs was similar in both groups ( FIG. 5E ).
5B shows that Adcy9 inactivation enhanced endothelium-dependent vasodilation in response ^{to increased shear stress (15 dynes/cm 2} ) compared to WT (42.3±7.1% vs. 28.2±6.3%, P=0.08).
5c and 5f show that both endothelial-dependent (Ach) and endothelial-dependent vasodilation (SNP) in the femoral artery of atherosclerotic animals (AAV8-Pcsk9D377Y and atherogenic diet) are increased in Adcy9 ^{Gt/Gt mice compared to WT mice.} It is shown that (P<0.05).
5D and 5G depict the relaxant dose response to ACh ( FIG. 5D ) and SNP ( FIG. 5G ) of aorta of animals treated with AAV8-Pcsk9 ^{D377Y and an atherosclerotic diet when Adcy9 Gt/Gt} is compared to WT mice. .
6A and 6D show that the nitric oxide synthase blocker L-NNA significantly inhibited ACh-induced vasodilation in both WT and Adcy9 ^Gt/Gt mice (P<0.01), whereas ^{flow-mediated vasodilation was not achieved in Adcy9 Gt/Gt} mice. It is shown that only numerically decreased.
6B and 6E show that the cyclooxygenase blocker meclofenamate or a cocktail of endothelial-dependent hyperpolarization blockers (TRAM-34 and apamine ) inhibited ACh-induced endothelial-dependent vasodilation in Adcy9 ^{Gt/Gt mice (both pathways).} P<0.01 for all) not in WT mice.
Figure 6c shows that the specificity of the Adcy9 mRNA signal by in situ hybridization in the femoral artery wall was confirmed by the absence of a dot as a negative control probe.
7A shows that Adcy9 ^Gt/Gt mice gained more body weight than WT animals during 16 weeks of atherosclerotic diet, reaching body weights of 45.1±2.4 g and 33.5±1.2 g, respectively (P<0.01).
Figure 7b shows that MRI performed at week 14 showed ^{that Adcy9 Gt/Gt} mice displayed more adipose tissue than WT mice.
Figure 7c shows doubling of total body adipose tissue volume in Adcy9 ^Gt/Gt mice (9.4±1.2 cm3) compared to WT (4.3±0.4 cm3, P<0.01).
7D depicts larger groin, perirenal ^{, epididymal and interscapular fat depots in Adcy9 Gt/Gt} mice compared to WT.
7E and 7F depict histological sections showing that Adcy9 inactivation results in hypertrophic adipocytes in epididymal white adipose tissue ( FIG. 7E ) and larger lipid droplets in interscapular brown adipose tissue ( FIG. 7F ).
Figure 8a shows that Adcy9Gt/Gt mice on atherosclerotic diet showed a significant increase in feed efficiency (1.2±0.1 g/100 kCal) compared to WT (0.6±0.1 g/100 kCal, P<0.01).
Figure 8b shows increased RR interval (indicating heart rate variability by telemetry) in Adcy9Gt/Gt mice (135±5 ms) compared to WT mice (123±4 ms, P=0.05).
8C shows lower nocturnal heart rate in Adcy9Gt/Gt mice (447±10 bpm) compared to WT mice (475±10 bpm, P=0.06). The pNN(6), which represents the rate at which the RR interval exceeded the antecedent interval by more than 6 ms and reflects parasympathetic nervous system activity17, was found in Adcy9Gt/Gt mice (21.6±2.4%) during the nocturnal period in WT (14.5±2.2%, P<0.05). ) was increased compared to
9A and 9C show that CETP ^WT and CETP ^Gt mice developed similar atherosclerotic lesions covering 11.8±1.8% and 8.6±1.9% of the intimal area, respectively (P=NS).
9B depicts the percentage of total aortic lesion area in WT, Adcy9 ^Gt/Gt , CETP ^WT and CETP ^{Gt mice.}
10A depicts vasodilation to ACh in the femoral artery from ^{atherosclerotic CETP WT} and CETP ^{Gt mice.}
10B depicts vasodilation for SNPs in femoral arteries from ^{atherosclerotic CETP WT} and CETP ^{Gt mice.}
11A depicts the progression of body weight upon arteriosclerosis treatment in WT, Adcy9 ^Gt/Gt , CETP ^WT and CETP ^{Gt mice.}
11B depicts adipose tissue volume on MRI in WT, Adcy9 ^Gt/Gt , CETP ^WT and CETP ^{Gt mice.}
12A depicts a mouse model of myocardial infarction. These mice have four different genotypes: WT (wild-type mice); Adcy9 ^Gt/Gt (Adyc9 gene capture mice); tgCETP ^+/- (transgenic mice carrying a copy of the CETP gene); and Adcy9 ^Gt/Gt - tgCETP ^+/- (Adyc9 gene capture mice carrying a copy of the CETP gene). All mice have a C57BL/6J genetic background.
12B is a diagram showing the ligation of the left ventricular anterior descending (LAD) artery using sutures used to mimic myocardial infarction induced by plaque formation.
12C depicts a surgical timeline of a mouse infarct model by ligating the LAD. Echocardiography (“Echo”) was performed at baseline 24 hours, 1 week, and 4 weeks after surgery.
13A depicts the Kruskal-Wallis test for age of mice with four genotypes at day 0.
13B shows the Kruskal-Wallis test of body weight (“BW”) of mice with four genotypes on day 0.
13C shows the survival of mice for 28 days. No differences in survival were observed between mice with the four genotypes.
Figure 14a (All mice) and Figure 14b (only in the living mouse) are four kinds of genotype (WT, Adcy9Gt / Gt, tgCETP +/- Adcy9Gt and / Gt - tgCETP ^+/-) fake or myocardial infarction induced with ( "MI") shows an echocardiographic wall motion score index (WMSI) analysis performed 24 hours after LAD-ligation for mice.
15 depicts WMSI correlated with serum cardiac troponin-I (cTn-I) at 24 hours.
16A shows that the reduced WMSI for ^{Adcy9 Gt/Gt} mice observed 24 h after LAD-ligation is maintained over time.
Figure 16b shows the four genotypes (WT, Adcy9 ^Gt / ^Gt , tgCETP ^+/- and Adcy9 ^Gt / ^Gt - Bidirectional repeated ANOVA analysis for myocardial infarction induced (“MI”) mice with tgCETP ^{+/- ) is shown (p<0.001).}
17A shows how the portion of the ischemic myocardium was calculated.
17B depicts the proportion of ischemic myocardium in mice with four genotypes.
18A shows how the hearts of mice with four genetic backgrounds were segmented for histological analysis.
18B depicts Masson's trichrome staining of the heart for infarct size estimation.
19A and 19B show the four genotypes (WT, Adcy9 ^Gt / ^Gt , tgCETP ^+/- and Adcy9 ^Gt / ^Gt − Infarct size reduction in mice with tgCETP ^{+/- ) is shown.}
19C shows that Adcy9 ^Gt/Gt MI mice have lower WMSI compared to mice with other genotypes.

Justice

An “effective amount” when used in connection with a CETP inhibitor and ADCY inhibitor is the total amount of a CETP inhibitor and ADCY inhibitor effective to treat or prevent a cardiovascular condition or reduce the risk of a cardiovascular event in a subject.

A “gene” is an ordered sequence of nucleotides located at a specific location on a specific chromosome that encodes a specific functional product and may include untranslated and untranscribed sequences in proximity to the coding region. Such non-coding sequences may contain regulatory sequences necessary for transcription and translation, such as sequences or introns, or may not yet have any function attributed to them beyond the generation of the SNP of interest.

The term “genotyping” refers to the determination of genetic information carried at one or more locations in an individual's genome. For example, genotyping may include determining an allele or alleles an individual possesses for a single SNP or determining an allele or alleles an individual possesses for a plurality of SNPs. For example, the nucleotide at rs 1967309 may be A in some individuals and G in others. An individual with an A in position has an A allele and an individual with a G has a G allele. In a diploid organism, an individual has two copies of the sequence comprising the polymorphic site, so the individual will have an A allele and a G allele, or alternatively two copies of the A allele or two copies of the G allele. can An individual with two copies of the G allele is homozygous for the G allele, an individual with two copies of the A allele is homozygous for the A allele, and an individual with one copy of each allele is heterozygous. Alleles are mainly referred to as A alleles, mainly major alleles and B alleles, mainly minor alleles. The genotype can be AA (homozygous A), BB (homozygous B) or AB (heterozygous).

The term "about" when used in reference to a referenced numerical expression means to add or subtract up to 10% of the referenced numerical expression to the referenced numerical expression. For example, the language "about 50" means 45 to 55.

Unless defined otherwise, the term "subject" as used herein refers to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig or non-human primate, such as a monkey, chimpanzee or is a baboon In some embodiments, the subject is a human. In some embodiments, the subject is an adult. In some embodiments, the subject is a child.

As used herein, the term “adult” refers to a human 18 years of age or older.

As used herein, the term “child” refers to a human between 1 and 18 years of age.

CEPT inhibitors

CETP inhibitors useful in the compositions and methods of the present invention include small molecules, anti-CETP antibodies and peptides that inhibit or repress CETP activity.

CETP inhibitors useful in the compositions and methods of the present invention include dalcetrapib, anacetrapib, evacetrapib, torcetrapib, BAY 60-5521, obisetrapib, BMS-795311, CP-800,569, DRL-17822, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, DLBS-1449 (Dexa Medica) and ATH-03 (Affris), and pharmaceutically acceptable salts of any of these. .

"Dalcetrapib" means S-[2-({[1-(2-ethylbutyl)cyclohexyl]carbonyl}amino)phenyl]-2-methylpropanethioate, JTT-705 or CAS 211513 Also known as -37-O. Dalcetrapib has the following structure:

"Anacetrapib" refers to (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-methoxy-5'-(propane) -2-yl)-4-(trifluoromethyl)[1,1'-biphenyl]-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one, (45,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-({2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl) ]-5-(trifluoromethyl)phenyl}methyl)-4-methyl-1,3-oxazolidin-2-one; MK-0859; or CAS 875446-37-0. Anacetrapib has the following structure:

"Evacetrapib" means trans-4-({(5S)-5-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(2-methyl-2H-tetrazol-5-yl) amino]-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzazepin-1-yl}methyl)cyclohexanecarboxylic acid, also referred to as LY2484595 or CAS 1186486-62-3 is known Evacetrapib has the following structure:

"Torcetrapib" refers to (2R,4S)-4-[(3,5-bistrifluoromethylbenzyl)methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-di refers to hydro-2H-quinoline-1-carboxylic acid ethyl ester, ethyl (2R,4S)-4-({[3,5-bis(trifluoromethyl)phenyl]methyl}(methoxycarbonyl)amino) -2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-1-carboxylate; CP-529,414; or CAS 262352-17-0. Torcetrapib has the following structure:

"BAY 60-5521" is (S)-4-cyclohexyl-2-cyclopentyl-3-((S)-fluoro(4-(trifluoromethyl)phenyl)methyl)-7,7-dimethyl) -5,6,7,8-tetrahydroquinolin-5-ol, also known as CAS 893409-49-9. BAY 60-5521 has the following structure:

"Obisetrapib" is 4-((2-((3,5-bis(trifluoromethyl)benzyl)(2R,4S)-1-(ethoxycarbonyl)-2-ethyl-6-(tri fluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrimidin-5-yl)oxy)butanoic acid, AMG-899, DEZ-001, TA-8995 or Also known as CAS 866399-87-3. Obisetrapib has the following structure:

"BMS795311" is (R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(2,2,3,3-tetrafluoroprop panoyl)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide, also known as CAS 939390-99-5. BMS795311 has the following structure:

"CP-800,569" is (2R)-3-[3-(4-chloro-3-ethylphenoxy)-n-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl] methyl]anilino]-1,1,1-trifluoropropan-2-ol. CP-800,569 has the following structure:

“DRL-17822” means CAS 1454689-50-9 and is disclosed in WO 2014128564 and WO 2014076568. DRL-17822 has the following structure:

"JNJ-28545595" is 1,1,1-trifluoro-3-[2-[3-(1,1,2,2-tetra-fluoroethoxy)phenyl]-5-(3-trifluoro Romethoxyphenyl)-3,4-dihydro-2H-quinolin-1-yl]-propan-2-ol.

"JNJ-28614872" is 1,1,1-trifluoro-3-[3-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-8-(3-tri Fluoromethoxy-phenyl)-2,3-dihydro-benzo[1,4]oxa-4-yl]-propan-2-ol.

The structures of JNJ-28545595 and JNJ-28614872 are as follows:

The structures of "BAY 19-4789" and "BAY 38-1315" are as follows:

Additional CETP inhibitors useful in the compositions and methods of the present invention include those disclosed in WO 2016/086453 or Chen et al., European Journal of Medicinal Chemistry , (2017) 139: 201-213 and have the structure:

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof.

and pharmaceutically acceptable salts thereof.

Additional CETP inhibitors useful in the compositions and methods of the present invention are disclosed in WO 2016/086453 or Chen et al and include, but are not limited to:

and pharmaceutically acceptable salts thereof.

Additional CETP inhibitors useful in the compositions and methods of the present invention include those disclosed in WO 2017/011279 and have the structure:

and pharmaceutically acceptable salts thereof.

Another CETP inhibitor useful in the compositions and methods of the present invention includes those disclosed in WO 2016/018729 and has the structure:

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof; and

and pharmaceutically acceptable salts thereof.

Additional CETP inhibitors useful in the compositions and methods of the present invention are disclosed in US 7,781,426, including but not limited to:

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof; and

and pharmaceutically acceptable salts thereof.

Additional CETP inhibitors useful in the compositions and methods of the present invention are disclosed in US 7,652,049, including but not limited to:

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof;

and pharmaceutically acceptable salts thereof; and

and pharmaceutically acceptable salts thereof.

Additional CETP inhibitors useful in the compositions and methods of the present invention are disclosed in US20150374675 A1 and include, but are not limited to:

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chlorothioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiopropionate;

S-[2-(1-Isopentylcyclohexanecarbonylamino)phenyl]phenoxy-thioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclopropanethiocarboxylate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;

S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]thioacetate;

S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-isopentylcyclopentaincarbonylamino)-phenyl]2,2-dimethylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;

O-methyl S-[2-(1-isopentylcyclohexanecarbonylaminophenyl monothiocarbonate;

S-[2-(1-methylcyclohexanecarbonylamino)phenyl]S-phenyldithiocarbonate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;

S-[2-(pivaloylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(2-cyclohexylpropionylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;

S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]disulfide;

2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonylamino)phenyl disulfide;

N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;

N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclohexanethiocarboxylate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiobenzoate;

S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;

S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;

bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]disulfide;

N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;

S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;

S-[2-1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;

S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate; and

S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]-1-acetyl-piperidine-4-thiocarboxylate and pharmaceutically acceptable salts thereof.

Additional examples of CETP inhibitors useful in the compositions and methods of the present invention include torcetrapib; dalcetrapib; anacetrapib; evacetrapib; obisetrapib; BMS-79531; CP-800,569; DRL-17822; JNJ-28545595; JNJ-28614872; BAY 19-4789; BAY 38-1315; 1,1,1-trifluoro-3-((3-phenoxyphenyl)(3-(1,1,2,2-tetrafluoroethoxy)benzyl)amino)propan-2-ol; (R)-3-((4-(4-chloro-3-ethylphenoxy)pyrimidin-2-yl)(3-(1,1,2,2-tetrafluoroethoxy)benzyl)amino) -1,1,1-trifluoropropan-2-ol; (R)-3-((3-(4-chloro-3-ethylphenoxy)phenyl)(3-(1,1,2,2-tetrafluoroethoxy)benzyl)amino)-1,1, 1-trifluoropropan-2-ol (CP-800,569); N-(4-(5,7-dimethylbenzo[d]oxazol-2-yl)phenyl)-2-(o-tolyloxy)acetamide; 2-(4-chloro-2,3-dimethylphenoxy)-N-(4-(5-cyanobenzo[d]oxazol-2-yl)phenyl)acetamide; N-(4-(5-chlorobenzo[d]oxazol-2-yl)phenyl)-2-(o-tolyloxy)acetamide; N-(4-(5-chlorobenzo[d]oxazol-2-yl)phenyl)-2-(o-tolyloxy)acetamide; N-(4-(5-cyano-7-methylbenzo[d]oxazol-2-yl)phenyl)-2-(o-tolyloxy)acetamide; N-(4-(5-cyano-7-(2-hydroxypropan-2-yl)benzo[d]oxazol-2-yl)phenyl)-2-(o-tolyloxy)acetamide; 2-(4-((2-(3,3,3-trifluoro-2-methyl-2-(trifluoromethyl)propoxy)ethyl)amino)phenyl)benzo[d]oxazole-5- carbonitrile; tert-butyl 4-(2-((4-(5-cyanobenzo[d]oxazol-2-yl)phenyl)amino)-2-oxoethoxy)piperidine-1-carboxylate; N-(4-(5-cyano-7-methylbenzo[d]oxazol-2-yl)phenyl)-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl ) acetamide; N-(4-(5-cyano-7-methylbenzo[d]oxazol-2-yl)phenyl)-2-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl ) acetamide; N-(4-(5-cyano-7-methylbenzo[d]oxazol-2-yl)phenyl)-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine -1-yl)acetamide; 4-(5-Cyano-7-methylbenzo[d]oxazol-2-yl)-N-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl) benzamide; 4-(5-Cyano-7-isopropylbenzo[d]oxazol-2-yl)-N-((1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4 -yl)methyl)benzamide; 4-(5-Cyano-7-isopropylbenzo[d]oxazol-2-yl)-N-((1-(5-phenylpyridin-2-yl)piperidin-4-yl)methyl) benzamide; 4-(5-Cyano-7-isopropylbenzo[d]oxazol-2-yl)-N-((1-(5-(2-isopropyl-5-methylphenyl)pyridin-2-yl)p peridin-4-yl)methyl)benzamide; 4-(5-Cyano-7-isopropylbenzo[d]oxazol-2-yl)-N-((1-(5-(5-fluoro-2-isopropylphenyl)pyridin-2-yl )piperidin-4-yl)methyl)benzamide; (R)-4-(5-cyano-7-isopropylbenzo[d]oxazol-2-yl)-N-((2-oxo-3-(5-(2-(trifluoromethoxy) phenyl)pyridin-2-yl)oxazolidin-5-yl)methyl)benzamide; (S)-4-(5-cyano-7-isopropylbenzo[d]oxazol-2-yl)-N-((2-oxo-3-(5-(2-(trifluoromethoxy) phenyl)pyridin-2-yl)oxazolidin-5-yl)methyl)benzamide; (R)-4-(5-cyano-7-isopropylbenzo[d]oxazol-2-yl)-N-((5-methyl-2-oxo-3-(5-(2-(tri fluoromethoxy)phenyl)pyridin-2-yl)oxazolidin-5-yl)methyl)benzamide; (S))-4-(5-cyano-7-isopropylbenzo[d]oxazol-2-yl)-N-((5-methyl-2-oxo-3-(5-(2-( trifluoromethoxy)phenyl)pyridin-2-yl)oxazolidin-5-yl)methyl)benzamide; N-((4-(4-(tert-butyl)phenyl)cyclohexyl)methyl)-4-(5-cyano-7-isopropylbenzo[d]oxazol-2-yl)benzamide; Methyl (3,5-bis(trifluoromethyl)benzyl)((5′-isopropyl-2′-methoxy-4-(trifluoromethyl)-[1,1′-biphenyl]-2- yl)methyl)carbamate; methyl (3,5-bis(trifluoromethyl)benzyl)(2-((ethoxycarbonyl)(propyl)amino)-5-(trifluoromethyl)benzyl)carbamate; methyl (3,5-bis(trifluoromethyl)benzyl)(2-(2-oxooxazolidin-3-yl)-5-(trifluoromethyl)benzyl)carbamate; methyl (3,5-bis(trifluoromethyl)benzyl)(2-(2-oxoimidazolidin-1-yl)-5-(trifluoromethyl)benzyl)carbamate; 4-(3,5-bis(trifluoromethyl)phenyl)-3-((5′-isopropyl-2′-methoxy-4-(trifluoromethyl)-[1,1′-biphenyl ]-2-yl)methyl)oxazolidin-2-one; (R)-4-(3,5-bis(trifluoromethyl)phenyl)-3-((5′-isopropyl-2′-methoxy-4-(trifluoromethyl)-[1,1 '-biphenyl]-2-yl)methyl)oxazolidin-2-one; (S)-4-(3,5-bis(trifluoromethyl)phenyl)-3-((5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-[1,1 '-biphenyl]-2-yl)methyl)oxazolidin-2-one; (4R,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((5′-isopropyl-2′-methoxy-4-(trifluoromethyl)-[1 ,1′-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one; (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((5′-isopropyl-2′-methoxy-4-(trifluoromethyl)-[1] ,1′-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one; (4R,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((5′-isopropyl-2′-methoxy-4-(trifluoromethyl)-[1 ,1′-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one; (4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-[1 ,1′-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one; 5-(2,6-bis(trifluoromethyl)pyridin-4-yl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl) )-[1,1′-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one; (4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-2'-hydroxy-5'-isopropyl-4-(trifluoro romethyl)-[1,1′-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one; (4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-2',3'-dihydroxy-5'-isopropyl-4 -(trifluoromethyl)-[1,1'-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one; (4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-2',3'-dihydroxy-5'-(2-hydroxyl) oxypropan-2-yl)-4-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one; (4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoro romethyl)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one; N-(6'-(((4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-2 -Methoxy-4',4'-dimethyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-N-methylacetamide; (S)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl) )-[1,1′-biphenyl]-2-yl)methyl)-4,4-dimethyloxazolidin-2-one; 3-(6'-(((4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-2 -Methoxy-4',4'-dimethyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2,2-dimethylpropane Mountain; 3-(3-(2-(((4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl) -6-methoxypyridin-3-yl)-4-methoxyphenyl)propanoic acid; 3'-(6-(azetidin-1-yl)-2-(((4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoxa Jolidin-3-yl)methyl)pyridin-3-yl)-5′-fluoro-4′-methoxy-2-methyl-[1,1′-biphenyl]-4-carboxylic acid; Isopropyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(2H-tetrazol-5-yl)amino)-2-ethyl-6-(trifluoromethyl) -3,4-dihydroquinoline-1(2H)-carboxylate; Isopropyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-2-ethyl-6-(tri fluoromethyl)-3,4-dihydroquinoline-1(2H)-carboxylate; Isopropyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(2-(2-cyanoethyl)-2H-tetrazol-5-yl)amino)-2- ethyl-6-(trifluoromethyl)-3,4-dihydroquinoline-1(2H)-carboxylate; Isopropyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(2-(2-hydroxyethyl)-2H-tetrazol-5-yl)amino)-2- ethyl-6-(trifluoromethyl)-3,4-dihydroquinoline-1(2H)-carboxylate; Isopropyl (2R,4S)-4-((2-(2-aminoethyl)-2H-tetrazol-5-yl)(3,5-bis(trifluoromethyl)benzyl)amino)-2-ethyl -6-(trifluoromethyl)-3,4-dihydroquinoline-1(2H)-carboxylate; Isopropyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(2-(2-hydroxypropyl)-2H-tetrazol-5-yl)amino)-2- ethyl-6-(trifluoromethyl)-3,4-dihydroquinoline-1(2H)-carboxylate; Ethyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-2-ethyl-6-(trifluoro romethyl)-3,4-dihydroquinoline-1(2H)-carboxylate; Ethyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-2-ethyl-8-methyl-6 -(trifluoromethyl)-3,4-dihydroquinoline-1(2H)-carboxylate; Ethyl (2R,4S)-4-(N-(3,5-bis(trifluoromethyl)benzyl)acetamido)-2-ethyl-6-(trifluoromethyl)-3,4-dihydro -1,5-naphthyridine-1(2H)-carboxylate; Ethyl (2R,4S)-4-(N-(3,5-bis(trifluoromethyl)benzyl)acetamido)-2-ethyl-6-methoxy-3,4-dihydro-1,5 -naphthyridine-1(2H)-carboxylate; Ethyl (2R,4S)-4-(N-(3,5-bis(trifluoromethyl)benzyl)acetamido)-6-(dimethylamino)-2-ethyl-3,4-dihydro- 1,5-naphthyridine-1(2H)-carboxylate; Ethyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-2-ethyl-6-(trifluoro Rhomethyl)-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate; Ethyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-2-ethyl-6-methoxy- 3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate; Ethyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-6-(dimethylamino)-2 -ethyl-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate; Isopropyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-2-ethyl-6-(tri Fluoromethyl)-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate; Isopropyl (2R,4S)-4-((3-chloro-5-(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-2-ethyl-6-( trifluoromethyl)-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate; Isopropyl (2R,4S)-4-((3,5-dichlorobenzyl)(2-methyl-2H-tetrazol-5-yl)amino)-2-ethyl-6-methyl-3,4-di hydro-1,5-naphthyridine-1(2H)-carboxylate; 5-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-N-(cyclopentylmethyl)-N-ethyl-1 ,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-amine; 6-(((2-(bis(cyclopropylmethyl)amino)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)methyl)(3,5 -bis(trifluoromethyl)benzyl)amino)benzo[d]oxazol-2(3H)-one; 3-(((3,5-bis(trifluoromethyl)benzyl)(5-morpholinopyrimidin-2-yl)amino)methyl)-N,N-bis(cyclopropylmethyl)-7,7 -dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-amine; Isopropyl (2R)-4-((3,5-bis(trifluoromethyl)benzyl)(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)- 2-ethylpyrrolidine-1-carboxylate; 3-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-bromo-N-(cyclopentylmethyl)- N-ethyl-6-methylpyridin-2-amine; 3-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-N-(cyclopentylmethyl)-N-ethyl-6 -methyl-5-(methylthio)pyridin-2-amine; ((2R)-4-((3,5-bis(trifluoromethyl)benzyl)(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2 -ethylpyrrolidin-1-yl)(cyclohexyl)methanone; (1r,4r)-4-(((2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4- (trifluoromethyl)phenyl)(ethyl)amino)methyl)cyclohexane-1-carboxylic acid; 3-((((3-((cyclopentylmethyl)(ethyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)(2-methyl-2H-tetrazole-5- yl)amino)methyl)-5-(trifluoromethyl)benzonitrile; (1R,4r)-4-(((2R,6S)-4-((3,5-bis(trifluoromethyl)benzyl)(5-(1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl)amino)-2,6-diethylpiperidine-1-carbonyl)oxy)cyclohexane-1-carboxylic acid; (1R,3R)-3-(((2R,6S)-4-((3,5-bis(trifluoromethyl)benzyl)(5-(1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl)amino)-2,6-diethylpiperidine-1-carbonyl)oxy)cyclobutane-1-carboxylic acid; 1-(2-((3,5-bis(trifluoromethyl)benzyl)(2-(ethyl(2-methoxyethyl)amino)benzyl)amino)pyrimidine-5-yl)piperidine-4 -carboxylic acids; 5-(((1-(3,5-bis(trifluoromethyl)phenyl)ethyl)(5-(2-(methylsulfonyl)ethoxy)pyrimidin-2-yl)amino)methyl)-N -(cyclopentylmethyl)-N-ethyl-1,3-dimethyl-1H-indazol-6-amine; N-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-N-(2-((cyclopentylmethyl)(ethyl)amino)-5-(trifluoromethyl)benzyl)- 5-(2-(methylsulfonyl)ethoxy)pyrimidin-2-amine; 4-((2-((3,5-bis(trifluoromethyl)benzyl)((3-((cyclopropylmethyl)(propyl)amino)quinolin-2-yl)methyl)amino)pyrimidine-5 -yl)oxy)butanoic acid; 3-((((3-((cyclopentylmethyl)(ethyl)amino)-6-methoxypyridin-2-yl)methyl)(5-(2-(methylsulfonyl)ethoxy)pyrimidine-2 -yl)amino)methyl)-5-(trifluoromethyl)benzonitrile; 2-((1S,4r)-4-(((2-((((S)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl)(5-(2-(methylsulf phonyl)ethoxy)pyrimidin-2-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(ethyl)amino)methyl)cyclohexyl)acetic acid; Ethyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(5-(2-(methylsulfonyl)ethoxy)pyrimidin-2-yl)amino)-2- ethyl-6-methoxy-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate; Ethyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(5-morpholinopyrimidin-2-yl)amino)-2-ethyl-6-(trifluoro methyl)-3,4-dihydroquinoline-1(2H)-carboxylate; Ethyl (2R,4S)-4-((3,5-bis(trifluoromethyl)benzyl)(5-morpholinopyrimidin-2-yl)amino)-2-ethyl-6-methoxy-3 ,4-Dihydro-1,5-naphthyridine-1(2H)-carboxylate; Isopropyl 5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7-methyl-8-(trifluoromethyl)-2 ,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate; Isopropyl 5-(N-(3,5-bis(trifluoromethyl)benzyl)acetamido)-7-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine- 1-carboxylate; 3-(5-(4-chloro-3-ethylphenoxy)-2-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-3,4-dihydroquinoline-1 ( 2H)-yl)-1,1,1-trifluoropropan-2-ol; (S)-1,1,1-trifluoro-3-((R)-2-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-5-(4-( trifluoromethoxy)phenyl)-3,4-dihydroquinolin-1(2H)-yl)propan-2-ol (JNJ-28545595); (S)-1,1,1-trifluoro-3-((S)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-8-(4-( trifluoromethoxy)phenyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-2-ol (JNJ-28614872); (R)-3-((R)-4-(3-(difluoromethoxy)benzyl)-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinoxaline-1 ( 2H)-yl)-1,1,1-trifluoropropan-2-ol; (S)-(2-cyclopentyl-4-ethyl-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(4-(trifluoromethyl )phenyl)methanone; (S)-2-cyclopentyl-3-((S)-fluoro(4-(trifluoromethyl)phenyl)methyl)-4-(4-fluorophenyl)-7,7-dimethyl-5 ,6,7,8-tetrahydroquinolin-5-ol (BAY 19-4789); (S)-3′-((S)-Fluoro(4-(trifluoromethyl)phenyl)methyl)-4′-(4-fluorophenyl)-2′-isopropyl-5′,8′ -dihydro-6'H-spiro[cyclobutane-1,7'-quinoline]-5'-ol (BAY 38-1315); (S)-4-cyclohexyl-2-cyclopentyl-3-((S)-hydroxy(4-(trifluoromethyl)phenyl)methyl)-7,7-dimethyl-5,6,7, 8-tetrahydroquinolin-5-ol; (S)-4-cyclohexyl-2-cyclopentyl-3-((S)-fluoro(4-(trifluoromethyl)phenyl)methyl)-7,7-dimethyl-5,6,7, 8-tetrahydroquinolin-5-ol; (S)-4-cyclohexyl-2-cyclopentyl-7,7-dimethyl-3-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroquinolin-5-ol ; (S)-6′-((S)-Fluoro(4-(trifluoromethyl)phenyl)methyl)-5′-(4-fluorophenyl)-7′-isopropyl-3′,4′ -dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-ol; (S)-6′-((S)-Fluoro(4-(trifluoromethyl)phenyl)methyl)-5′-(4-fluorophenyl)-7′-isopropyl-3′,4′ -dihydrospiro[cyclopropane-1,2'-pyrano[2,3-b]pyridin]-4'-ol; (S)-5′-(4-fluorophenyl)-6′-((S)-hydroxy(4-(trifluoromethyl)phenyl)methyl)-7′-isopropyl-3′,4′ -dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-ol; (S)-5′-(4-fluorophenyl)-6′-((S)-hydroxy(4-(trifluoromethyl)phenyl)methyl)-7′-isopropyl-3′,4′ -dihydrospiro[cyclopropane-1,2'-pyrano[2,3-b]pyridin]-4'-ol; (S)-(2-cyclopentyl-5-hydroxy-4-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(4-(trifluoro methyl)phenyl)methanone; (S)-(2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(penta-1,3-dien-1-yl)-5,6,7 with dihydrogen; 8-tetrahydroquinolin-3-yl)(4-(trifluoromethyl)phenyl)methanone compound (1:3); (S)-(2-cyclopentyl-4-(hexa-1,3,5-trien-1-yl)-5-hydroxy-7,7-dimethyl-5,6 with dihydrogen; 7,8-tetrahydroquinolin-3-yl)(4-(trifluoromethyl)phenyl)methanone compound (1:5); (S)-(2'-cyclopentyl-5'-hydroxy-4'-isopropyl-5',8'-dihydro-6'H-spiro[cyclobutane-1,7'-quinoline]- 3′-yl)(4-(trifluoromethyl)phenyl)methanone; (S)-(2'-cyclopentyl-5'-hydroxy-4'-(penta-1,3-dien-1-yl)-5',8'-dihydro-6 with dihydrogen 'H-spiro[cyclobutane-1,7'-quinolin]-3'-yl)(4-(trifluoromethyl)phenyl)methanone compound (1:3); (S)-(2'-cyclopentyl-4'-(hexa-1,3,5-trien-1-yl)-5'-hydroxy-5',8'-dihydro with dihydrogen -6'H-spiro[cyclobutane-1,7'-quinolin]-3'-yl)(4-(trifluoromethyl)phenyl)methanone compound (1:5); (S)-(4-Cyclohexyl-5-hydroxy-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(4-(trifluoro methyl)phenyl)methanone; (S)-(4'-cyclohexyl-5'-hydroxy-2'-isopropyl-5',8'-dihydro-6'H-spiro[cyclobutane-1,7'-quinoline]- 3′-yl)(4-(trifluoromethyl)phenyl)methanone; (S)-4-(4,4-difluorocyclohexyl)-3-((S)-fluoro(4-(trifluoromethyl)phenyl)methyl)-2-(1-(5-( 3-hydroxy-3-methylbutoxy)pyrimidin-2-yl)piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol; N-((2-(4-((S)-4-(4,4-difluorocyclohexyl)-3-((S)-fluoro(4-(trifluoromethyl)phenyl)methyl) -5-Hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)piperidin-1-yl)pyrimidin-5-yl)methyl)-N-methyl methanesulfonamide; (S)-4-(4,4-difluorocyclohexyl)-3-((S)-fluoro(4-(trifluoromethyl)phenyl)methyl)-7,7-dimethyl-2- (1-(5-((1-methylpiperidin-4-yl)oxy)pyrimidin-2-yl)piperidin-4-yl)-5,6,7,8-tetrahydroquinoline-5 -all; (S)-6′-((R)-Fluoro(4-(trifluoromethyl)phenyl)methyl)-5′-(4-fluorophenyl)-7′-isopropyl-3′,4′ -dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-ol; (S)-6′-((R)-Fluoro(4-(trifluoromethyl)phenyl)methyl)-5′-(4-fluorophenyl)-7′-isopropyl-3′,4′ -dihydrospiro[cyclopropane-1,2'-pyrano[2,3-b]pyridin]-4'-ol; 2-phenyl-1-(pyridin-2-yl)-1-(3-(trifluoromethyl)phenyl)ethyl 3,3-dimethylbutanoate; (S)-1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2- phenylethyl)-3-cyclopentylurea; (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2- phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide; 1-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2- phenylethyl)-3-((R)-3,3-difluorocyclopentyl)urea; (S)-1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2- phenylethyl)-3-(3,3-difluorocyclobutyl)urea; (3'R,9'S)-4'-Isopropyl-7',7'-dimethyl-3'-(4-(trifluoromethyl)phenyl)-6',7',8',9'- tetrahydro-3′H-spiro[cyclopentane-1,1′-furo[3,4-c]quinolin]-9′-ol; (3R,9S)-4-isopropyl-7,7-dimethyl-3-(4-(trifluoromethyl)phenyl)-2',3',5',6,6',7,8, 9-octahydro-3H-spiro[furo[3,4-c]quinolin-1,4'-pyran]-9-ol; (3'R,6'R,9'S)-4'-Isopropyl-3'-(4-(trifluoromethyl)phenyl)-2'',3',3'',5'',6' ,6'',8',9'-octahydrodispiro[cyclopropane-1,7'-furo[3,4-c]quinoline-1',4''-pyran]-6',9' - diol; (S)-1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2- phenylethyl)-3-(2,2,2-trifluoroethyl)urea; (R)-3-(((S)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy) phenyl)-4-phenylbutyl)amino)-1,1,1-trifluoropropan-2-ol; (R)-3-(((R)-2-(5-chloropyridin-2-yl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy) phenyl)-3-phenylpropyl)amino)-1,1,1-trifluoropropan-2-ol; 5-chloro-6-fluoro-N-(3-(trifluoromethyl)phenethyl)-N-(4-(trimethylsilyl)benzyl)-1H-indole-7-carboxamide; 5-chloro-6-fluoro-N-(3-(trifluoromethoxy)phenethyl)-N-(4-(trimethylsilyl)benzyl)-1H-indole-7-carboxamide; dacetrapib; N-(4-(tert-butyl)benzyl)-5-chloro-N-(3-(trifluoromethyl)phenethyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide ; 3,5-dichloro-N-(4-chlorophenethyl)-N-(4-(perfluoropropan-2-yl)benzyl)benzamide; and N-((5-(tert-butyl)thiophen-2-yl)methyl)-5-chloro-2-(methylamino)-N-(4-(trifluoromethyl)phenethyl)nicotinamide; and pharmaceutically acceptable salts thereof.

In some embodiments, the CETP inhibitor is an antibody or peptide. U.S. Patent No. 5,519,001, incorporated herein by reference, describes a 36 amino acid peptide derived from baboon apo C-1 that inhibits CETP activity. Cho et al. ( Biochim. Biophys. Acta (1998) 1391:133-144) describe peptides from porcine plasma that inhibit human CETP. Bonin et al. ( J. Peptide Res. (1998) 51, 216-225) disclose decapeptide inhibitors of CETP. Depth peptide fungal metabolites are described in Hedge et al. in Bioorg. Med. Chem. Lett., (1998) 8:1277-80 as CETP inhibitors. Anti-CETP antibodies are described in WO20133075040 A1, which is incorporated herein by reference.

ADCY inhibitors

ADCY inhibitors can be small molecules, anti-ADCY antibodies and peptides that inhibit or repress adenylate cyclase expression or activity. In some embodiments, the ADCY inhibitor inhibits or represses adenylate cyclase expression or activity of one or more of ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 and ADCY10. In some embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.

The following table lists exemplary ADCY inhibitors. Such ADCY inhibitors and pharmaceutically acceptable salts thereof are useful in the methods and compositions of the present invention. The structure of each compound is shown immediately to the right of its name.

Additional ADCY inhibitors useful in the compositions and methods of the present invention are described in Dessauer et al. Pharmacol Rev, (2017) 69 (2): 93-139 and has the structure:

and pharmaceutically acceptable salts thereof.

Additional examples of small molecule ADCY inhibitors include, but are not limited to: SQ22536 (9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotrides-1-en-2-amine); 2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone; 4.2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; Cl-ANT-ATP; Cl-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; Bis-MANT-ATP; Bis-MANT-ITP; Bis-MANT-CTP; Bis-MANT-IDP; Bis-MANT-IMP; Bis-Cl-ANT-ATP; Bis-Cl-ANT-ITP; Bis-Br-ANT-ATP; Bis-Br-ANT-ITP; Bis-Pr-ANT-ATP; Bis-Pr-ANT-ITP; Bis-AcNH-ANT-ATP; Bis-AcNH-ANT-ITP; NKY80; vidarabine; 2', 5'-dd-3'-ATP; AraAde; PMC6; NB001; BODIPY-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; and pharmaceutically acceptable salts thereof.

Exemplary ADCY inhibitor peptides useful in the compositions and methods of the present invention include adrenocorticotropic hormone; brain natriuretic peptide (BNP); and pituitary adenylate cyclase activating polypeptides.

pharmaceutically acceptable salts

Pharmaceutically acceptable salts include, for example, acid-addition salts and base-addition salts. The acid forming the acid-addition salt may be an organic acid or an inorganic acid. The base forming the base-addition salt may be an organic base or an inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt. In some embodiments, the pharmaceutically acceptable salt is an ammonium salt.

Acid-addition salts can occur by adding an acid to the free base form of a compound useful in the compositions and methods of the present invention. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. Non-limiting examples of suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, nicotinic acid, isonicotinic acid, lactic acid, salicylic acid, 4-amino salicylic acid, tartaric acid, ascorbic acid, gentic acid, gluconic acid , glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, citric acid, oxalic acid, maleic acid, hydroxy maleic acid, methyl maleic acid, glycolic acid, malic acid, cinnamic acid , mandelic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, phenylacetic acid, N-cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-hydride Roxyethanesulfonic acid, ethane-1,2-disulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 2-phosphoglyceric acid, 3-phospho polyglyceric acid, glucose-6-phosphate and amino acids.

Non-limiting examples of suitable acid addition salts include hydrochloride, hydrogen bromide, hydrogen iodide, nitrate, nitrite, sulfate, sulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, carbonate, bicarbonate, nicotinate, isonicotinate, lactic acid Salts, salicylates, 4-aminosalicylates, tartrates, ascorbates, genticylates, glucosate, glucarates, saccharates, formates, benzoates, glutamates, pantothenates, acetates, propions , butyrate, fumarate, succinate, citrate, oxalate, maleate, hydroxymaleate, methyl maleate, glycolate, malate, cinnarate, mandelate, 2-phenoxybenzoate, 2-acetoxy Benzoate, embonate, phenyl acetate, N-cyclohexyl sulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, ethane-1,2 -Disulfonate, 4-methylbenzenesulfonate, naphthalene-2-sulfonate, naphthalene-1,5-disulfonate, 2-phosphoglycerate, 3-phosphoglycerate, glucose-6-anic acid salts salts and amino acid salts.

Metal salts can occur by adding an inorganic base to a compound having a carboxyl group. Inorganic bases may include, for example, metal cations paired with basic counterions such as hydroxides, carbonates, bicarbonates or phosphates. The metal may be an alkali metal, an alkaline earth metal, a transition metal or a main group metal. Non-limiting examples of suitable metals include lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium and zinc.

Non-limiting examples of suitable metal salts include lithium salts, sodium salts, potassium salts, cesium salts, cerium salts, magnesium salts, manganese salts, iron salts, calcium salts, strontium salts, cobalt salts, titanium salts, aluminum salts, copper salts, cadmium salts. salts and zinc salts.

Ammonium salts can be generated by adding ammonia or an organic amine to a compound having a carboxyl group. Non-limiting examples of suitable organic amines include triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N -Ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, imidazole, pyrazine, piperazine, ethylenediamine, N,N'-dibenzylethylenediamine, procaine, chloroprocaine, choline, dicyclohexyl amine and N-methylglucamine.

Non-limiting examples of suitable ammonium salts include triethylammonium salt, diisopropylammonium salt, ethanolammonium salt, diethanolammonium salt, triethanolammonium salt, morpholinium salt, N-methylmorpholinium salt, piperidinium salt, N-methylpiperidinium salt, N-ethylpiperidinium salt, dibenzylammonium salt, piperazinium salt, pyridinium salt, pyrazolium salt, imidazolium salt, pyrazinium salt, ethylenediammonium salt, N,N'-dibenzylethylenediammonium salt, procaine salt, chloroprocaine salt, choline salt, dicyclohexylammonium salt and N-methylglucamine salt.

Methods for treating or preventing cardiovascular abnormalities

The present invention relates to a method comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor.

In certain embodiments, the cardiovascular abnormality is acute coronary syndrome (ACS), atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial- Hypercholesterolemia, angina pectoris, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angiogenic restenosis, hypertension, cardiovascular disease, coronary heart disease, coronary artery disease, hyperlipidemia, hyperlipoproteinemia or diabetes, obesity or endotoxin It is a vascular complication of hemorrhage.

In certain embodiments, administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. In some embodiments, each of the CETP inhibitor and ADCY inhibitor is in a separate composition. In some embodiments, the CETP inhibitor and ADCY inhibitor are present in the same composition.

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine); 2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); 2-Amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)- quinazolinone, 4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; C1-ANT-ATP; C1-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; bis-MANT-ATP; bis-MANT-ITP; bis-MANT-CTP; bis-MANT-IDP; bis-MANT-IMP; bis-Cl-ANT-ATP; bis-Cl-ANT-ITP; bis-Br-ANT-ATP; bis-Br-ANT-ITP; bis-Pr-ANT-ATP; bis-Pr-ANT-ITP; bis-AcNH-ANT-ATP; bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP; araade; PMC6; NB001; Body P-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylic acid cyclase-activating polypeptide; or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

Another aspect of the invention provides a method of treating or preventing a cardiovascular condition comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has reduced expression or activity of ADCY compared to a control level. level, wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor.

In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, and the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or any pharmaceutically acceptable salts.

In some embodiments, ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these .

In certain embodiments, the control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY in a subject who does not respond positively to treatment with a CETP inhibitor in the absence of the ADCY inhibitor. In certain embodiments, the decreased expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene in the subject. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9.

Activity levels of ADCY can be detected using techniques known in the art. For example, adenylate cyclase assays are described in Salomon et al., (1974) Analytical Biochemistry , 58(2): 541-548; Wiegn et al., (1993) Anal Biochem. 208(2):217-22; and Storm et al., (1998) Neuron , 20:1199-1210.

In some embodiments, the expression level of ADCY is determined at the protein expression level. In some embodiments, protein expression levels of ADCY are assayed using specific antibody and protein assays. Any suitable method or assay can be used to measure ADCY protein expression levels in a biological sample from a subject. Numerous antibody-based detection formats are well known in the art and include ELISA (enzyme linked immunosorbent assay), radioimmunoassay, immunoblot, western blot, flow cytometry, immunofluorescence assay, immunoprecipitation, protein A assay, immunoelectrophoretic assay. and other related technologies. In some embodiments, antibody binding is detected by detecting a label on the primary antibody. In other embodiments, the primary antibody is detected by detecting binding of the secondary antibody or reagent to the primary antibody. In a further embodiment, the secondary antibody is labeled. Many means for detecting binding in an immunoassay are known in the art and are within the scope of the kits, assays and methods described herein. Antibodies specific for ADCY may be provided as a diagnostic kit comprising one or more of these procedures to quantify ADCY expression. Kits may include other components, packaging, instructions or other materials to aid in protein quantification and use of the kit.

Anti-ADCY antibodies as described herein can be prepared by inoculation of appropriate animals with polypeptides or antigenic fragments, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and/or nucleic acids encoding such anti-ADCY antibodies. It can be prepared commercially or routinely according to methods such as, but not limited to, expressing recombinant cells. Immunization of animals with purified recombinant ADCY or a peptide fragment thereof is an example of a method for producing anti-ADCY antibodies. Similarly, immunization of animals with purified recombinant ADCY or peptide fragments thereof is an example of a method for making anti-ADCY antibodies.

In another embodiment, the level of ADCY is assayed at the mRNA level. For example, RT-PCR and a pair of specific primers may be used. mRNA is prepared and analyzed according to well-established protocols.

In certain embodiments, the reduced expression or activity level of ADCY in the subject is tissue or cell type specific. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9.

In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level.

In some embodiments, the subject of the method is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a human child.

In certain embodiments, the cardiovascular disorder is acute coronary syndrome (ACS), atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial- Hypercholesterolemia, angina pectoris, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angiogenic restenosis, hypertension, cardiovascular disease, coronary heart disease, coronary artery disease, hyperlipidemia, hyperlipoproteinemia or diabetes, obesity or endotoxin It is a vascular complication of hemorrhage.

In certain embodiments, the subject has acute coronary syndrome (ACS).

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. In another embodiment, the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotrides-1-en-2-amine); Compounds such as 7,8-dihydro-5(6H)-quinonolinone derivatives disclosed in Japanese Patent Application No. 2001-153954 (preferably 2-amino-7-(4-chlorophenyl)-7,8-di Hydro-5(6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7 ,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; (2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; Cl-ANT-ATP; Cl-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; Bis-MANT-ATP; Bis-MANT-ITP; Bis-MANT-CTP; Bis-MANT-IDP; Bis-MANT-IMP; Bis-Cl-ANT-ATP; Bis-Cl-ANT-ITP; Bis-Br-ANT-ATP; Bis-Br-ANT-ITP; Bis-Pr-ANT-ATP; Bis-Pr-ANT-ITP; Bis-AcNH-ANT-ATP; Bis-AcNH-ANT-ITP; NKY80; vidarabine; 2', 5'-dd-3'-ATP; AraAde; PMC6; NB001; BODIPY-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; or a pharmaceutically acceptable salt thereof.

In some embodiments, the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylate cyclase activating polypeptide.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

The invention further provides a method of treating or preventing a cardiovascular condition comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ -28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG , rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs204861182/AA, rs2238448/TT /GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

The present invention also provides a method of treating or preventing a cardiovascular condition comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872 , BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject /AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT is known In some embodiments, the subject is known to have the genotype rs1967309/AG.

The present invention also provides a method of treating or preventing a cardiovascular condition comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872 , BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject /GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC , rs2531971/CC, or rs12599911/TT.

Methods for determining whether a subject has a particular genotype are well known to those skilled in the art, see eg WO 2014/154606A1 and WO 2016/016157A1.

How to reduce the risk of cardiovascular events

The present invention relates to a method comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor.

In certain embodiments, administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. In some embodiments, each of the CETP inhibitor and ADCY inhibitor is in a separate composition. In some embodiments, the CETP inhibitor and ADCY inhibitor are present in the same composition.

The invention further provides a method of reducing the risk of a cardiovascular event comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has a reduced expression or activity level of ADCY compared to a control level. , wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor.

In certain embodiments, the control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY in a subject who does not respond positively to treatment with a CETP inhibitor in the absence of the ADCY inhibitor. In certain embodiments, the decreased expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene in the subject. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9. Methods for measuring the expression or activity level of ADCY are disclosed herein.

In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8 or ADCY10, and the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311 , CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or any pharmaceutically acceptable thereof possible salts.

In some embodiments, ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of these am.

In certain embodiments, the cardiovascular event is coronary heart disease, cardiac arrest, myocardial infarction, ischemic stroke, congestive heart failure, sudden cardiac death, cerebral infarction, syncope, transient ischemic attack, angina pectoris, or coronary revascularization.

In certain embodiments, the cardiovascular event is an adverse cardiovascular event, eg, coronary heart disease, death, cardiac arrest, myocardial infarction, ischemic stroke, angina pectoris, or coronary revascularization. In some embodiments, the cardiac arrest is resuscitated cardiac arrest. In some embodiments, the myocardial infarction is nonfatal myocardial infarction. In some embodiments, the ischemic stroke is a nonfatal ischemic stroke. In some embodiments, the angina is unstable angina. In some embodiments, the coronary revascularization is unexpected coronary revascularization.

In certain embodiments, the subject has acute coronary syndrome (ACS).

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. In another embodiment, the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotrides-1-en-2-amine); Compounds such as 7,8-dihydro-5(6H)-quinonolinone derivatives disclosed in Japanese Patent Application No. 2001-153954 (preferably 2-amino-7-(4-chlorophenyl)-7,8-di Hydro-5(6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7 ,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; (2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; Cl-ANT-ATP; Cl-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; Bis-MANT-ATP; Bis-MANT-ITP; Bis-MANT-CTP; Bis-MANT-IDP; Bis-MANT-IMP; Bis-Cl-ANT-ATP; Bis-Cl-ANT-ITP; Bis-Br-ANT-ATP; Bis-Br-ANT-ITP; Bis-Pr-ANT-ATP; Bis-Pr-ANT-ITP; Bis-AcNH-ANT-ATP; Bis-AcNH-ANT-ITP; NKY80; vidarabine; 2', 5'-dd-3'-ATP; AraAde; PMC6; NB001; BODIPY-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; or a pharmaceutically acceptable salt thereof.

In some embodiments, the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylate cyclase activating polypeptide.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

The invention further provides a method of reducing the risk of a cardiovascular event comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ -28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG , rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs204861182/AA, rs2238448/TT /GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

The present invention also provides a method of reducing the risk of a cardiovascular event comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872 , BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject /AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT is known In some embodiments, the subject is known to have the genotype rs1967309/AG.

The present invention also provides a method of reducing the risk of a cardiovascular event comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872 , BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject /GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC , rs2531971/CC, or rs12599911/TT.

How to treat or prevent congestive heart failure

The present invention relates to a method comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

In certain embodiments, administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. In some embodiments, each of the CETP inhibitor and ADCY inhibitor is in a separate composition. In some embodiments, the CETP inhibitor and ADCY inhibitor are present in the same composition.

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine); 2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); 2-Amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)- Quinazolinone, 4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8 -dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; C1-ANT-ATP; C1-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; bis-MANT-ATP; bis-MANT-ITP; bis-MANT-CTP; bis-MANT-IDP; bis-MANT-IMP; bis-Cl-ANT-ATP; bis-Cl-ANT-ITP; bis-Br-ANT-ATP; bis-Br-ANT-ITP; bis-Pr-ANT-ATP; bis-Pr-ANT-ITP; bis-AcNH-ANT-ATP; bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP; araade; PMC6; NB001; Body P-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylic acid cyclase-activating polypeptide; or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

Another aspect of the invention provides a method of treating or preventing congestive heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has reduced expression of ADCY or It is known to have an activity level, wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor.

In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, and the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or any pharmaceutically thereof acceptable salts.

In some embodiments, ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these .

In certain embodiments, the control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY in a subject who does not respond positively to treatment with a CETP inhibitor in the absence of the ADCY inhibitor. In certain embodiments, the decreased expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene in the subject. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9.

Activity levels of ADCY can be detected using techniques known in the art. For example, adenylate cyclase assays are described in Salomon et al., (1974) Analytical Biochemistry , 58(2): 541-548; Wiegn et al., (1993) Anal Biochem. 208(2):217-22; and Storm et al., (1998) Neuron , 20:1199-1210.

In some embodiments, the expression level of ADCY is determined at the protein expression level. In some embodiments, protein expression levels of ADCY are assayed using specific antibody and protein assays. Any suitable method or assay can be used to measure ADCY protein expression levels in a biological sample from a subject. Numerous antibody-based detection formats are well known in the art and include ELISA (enzyme linked immunosorbent assay), radioimmunoassay, immunoblot, western blot, flow cytometry, immunofluorescence assay, immunoprecipitation, protein A assay, immunoelectrophoretic assay. and other related technologies. In some embodiments, antibody binding is detected by detecting a label on the primary antibody. In other embodiments, the primary antibody is detected by detecting binding of the secondary antibody or reagent to the primary antibody. In a further embodiment, the secondary antibody is labeled. Many means for detecting binding in an immunoassay are known in the art and are within the scope of the kits, assays and methods described herein. Antibodies specific for ADCY may be provided as a diagnostic kit comprising one or more of these procedures to quantify ADCY expression. Kits may include other components, packaging, instructions or other materials to aid in protein quantification and use of the kit.

Anti-ADCY antibodies as described herein can be prepared by inoculation of appropriate animals with polypeptides or antigenic fragments, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and/or nucleic acids encoding such anti-ADCY antibodies. It can be prepared commercially or routinely according to methods such as, but not limited to, expressing recombinant cells. Immunization of animals with purified recombinant ADCY or a peptide fragment thereof is an example of a method for producing anti-ADCY antibodies. Similarly, immunization of animals with purified recombinant ADCY or peptide fragments thereof is an example of a method for making anti-ADCY antibodies.

In another embodiment, the level of ADCY is assayed at the mRNA level. For example, RT-PCR and a pair of specific primers may be used. mRNA is prepared and analyzed according to well-established protocols.

In certain embodiments, the reduced expression or activity level of ADCY in the subject is tissue or cell type specific. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9.

In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level.

In some embodiments, the subject of the method is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a human child.

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. In another embodiment, the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotrides-1-en-2-amine); Compounds such as 7,8-dihydro-5(6H)-quinonolinone derivatives disclosed in Japanese Patent Application No. 2001-153954 (preferably 2-amino-7-(4-chlorophenyl)-7,8-di Hydro-5(6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7 ,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; (2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; Cl-ANT-ATP; Cl-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; Bis-MANT-ATP; Bis-MANT-ITP; Bis-MANT-CTP; Bis-MANT-IDP; Bis-MANT-IMP; Bis-Cl-ANT-ATP; Bis-Cl-ANT-ITP; Bis-Br-ANT-ATP; Bis-Br-ANT-ITP; Bis-Pr-ANT-ATP; Bis-Pr-ANT-ITP; Bis-AcNH-ANT-ATP; Bis-AcNH-ANT-ITP; NKY80; vidarabine; 2', 5'-dd-3'-ATP; AraAde; PMC6; NB001; BODIPY-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; or a pharmaceutically acceptable salt thereof.

In some embodiments, the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylate cyclase activating polypeptide.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

The invention further provides a method of treating or preventing congestive heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595; JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/ GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

The invention further provides a method of treating or preventing congestive heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595; JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/ AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs is known to have In some embodiments, the subject is known to have the genotype rs1967309/AG. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

The present invention also provides a method of treating or preventing congestive heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ- 28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448 CC, rs2531971/CC, or rs12599911/TT. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

How to Reduce Your Risk of Congestive Heart Failure

The present invention relates to a method comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

In certain embodiments, administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. In some embodiments, each of the CETP inhibitor and ADCY inhibitor is in a separate composition. In some embodiments, the CETP inhibitor and ADCY inhibitor are present in the same composition.

The present invention provides a method of reducing the risk of congestive heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has a reduced expression or activity level of ADCY compared to a control level. wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

In certain embodiments, the control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY in a subject who does not respond positively to treatment with a CETP inhibitor in the absence of the ADCY inhibitor. In certain embodiments, the decreased expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene in the subject. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9. Methods for measuring the expression or activity level of ADCY are disclosed herein.

In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, and the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or any pharmaceutically thereof acceptable salts.

In some embodiments, ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these .

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. In another embodiment, the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotrides-1-en-2-amine); Compounds such as 7,8-dihydro-5(6H)-quinonolinone derivatives disclosed in Japanese Patent Application No. 2001-153954 (preferably 2-amino-7-(4-chlorophenyl)-7,8-di Hydro-5(6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7 ,8-dihydro-5(6H)-quinazolinone;4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7- (2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; Cl-ANT-ATP; Cl-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; Bis-MANT-ATP; Bis-MANT-ITP; Bis-MANT-CTP; Bis-MANT-IDP; Bis-MANT-IMP; Bis-Cl-ANT-ATP; Bis-Cl-ANT-ITP; Bis-Br-ANT-ATP; Bis-Br-ANT-ITP; Bis-Pr-ANT-ATP; Bis-Pr-ANT-ITP; Bis-AcNH-ANT-ATP; Bis-AcNH-ANT-ITP; NKY80; vidarabine; 2', 5'-dd-3'-ATP; AraAde; PMC6; NB001; BODIPY-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; or a pharmaceutically acceptable salt thereof.

In some embodiments, the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylate cyclase activating polypeptide.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

The invention further provides a method of reducing the risk of congestive heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595; JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/ GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

The invention further provides a method of reducing the risk of congestive heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595; JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/ AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs is known to have In some embodiments, the subject is known to have the genotype rs1967309/AG. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

The invention also provides a method of reducing the risk of congestive heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ- 28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448 CC, rs2531971/CC, or rs12599911/TT. In certain embodiments, the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.

How to treat or prevent ventricular systolic insufficiency

The present invention relates to a method comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor. In certain embodiments, the ventricular systolic insufficiency is left ventricular systolic insufficiency. In certain embodiments, the ventricular insufficiency is right ventricular systolic insufficiency.

In certain embodiments, administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. In some embodiments, each of the CETP inhibitor and ADCY inhibitor is in a separate composition. In some embodiments, the CETP inhibitor and ADCY inhibitor are present in the same composition.

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine); 2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); 2-Amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)- Quinazolinone, 4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8 -dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; C1-ANT-ATP; C1-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; bis-MANT-ATP; bis-MANT-ITP; bis-MANT-CTP; bis-MANT-IDP; bis-MANT-IMP; bis-Cl-ANT-ATP; bis-Cl-ANT-ITP; bis-Br-ANT-ATP; bis-Br-ANT-ITP; bis-Pr-ANT-ATP; bis-Pr-ANT-ITP; bis-AcNH-ANT-ATP; bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP; araade; PMC6; NB001; Body P-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylic acid cyclase-activating polypeptide; or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

Another aspect of the invention provides a method of treating or preventing ventricular systolic insufficiency comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has reduced expression of ADCY compared to a control level. or activity level, wherein reduced expression or activity level of ADCY indicates that the subject will benefit from administration of the CETP inhibitor. In certain embodiments, the ventricular systolic insufficiency is left ventricular systolic insufficiency. In certain embodiments, the ventricular systolic insufficiency is right ventricular systolic insufficiency.

In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, and the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or any pharmaceutically acceptable salts.

In some embodiments, ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these .

In certain embodiments, the control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY in a subject who does not respond positively to treatment with a CETP inhibitor in the absence of the ADCY inhibitor. In certain embodiments, the decreased expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene in the subject. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9.

Activity levels of ADCY can be detected using techniques known in the art. For example, adenylate cyclase assays are described in Salomon et al., (1974) Analytical Biochemistry , 58(2): 541-548; Wiegn et al., (1993) Anal Biochem. 208(2):217-22; and Storm et al., (1998) Neuron , 20:1199-1210.

In some embodiments, the expression level of ADCY is determined at the protein expression level. In some embodiments, protein expression levels of ADCY are assayed using specific antibody and protein assays. Any suitable method or assay can be used to measure ADCY protein expression levels in a biological sample from a subject. Numerous antibody-based detection formats are well known in the art and include ELISA (enzyme linked immunosorbent assay), radioimmunoassay, immunoblot, western blot, flow cytometry, immunofluorescence assay, immunoprecipitation, protein A assay, immunoelectrophoretic assay. and other related technologies. In some embodiments, antibody binding is detected by detecting a label on the primary antibody. In other embodiments, the primary antibody is detected by detecting binding of the secondary antibody or reagent to the primary antibody. In a further embodiment, the secondary antibody is labeled. Many means for detecting binding in an immunoassay are known in the art and are within the scope of the kits, assays and methods described herein. Antibodies specific for ADCY may be provided as a diagnostic kit comprising one or more of these procedures to quantify ADCY expression. Kits may include other components, packaging, instructions or other materials to aid in protein quantification and use of the kit.

Anti-ADCY antibodies as described herein can be prepared by inoculation of appropriate animals with polypeptides or antigenic fragments, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and/or nucleic acids encoding such anti-ADCY antibodies. It can be prepared commercially or routinely according to methods such as, but not limited to, expressing recombinant cells. Immunization of animals with purified recombinant ADCY or a peptide fragment thereof is an example of a method for producing anti-ADCY antibodies. Similarly, immunization of animals with purified recombinant ADCY or peptide fragments thereof is an example of a method for making anti-ADCY antibodies.

In another embodiment, the level of ADCY is assayed at the mRNA level. For example, RT-PCR and a pair of specific primers may be used. mRNA is prepared and analyzed according to well-established protocols.

In certain embodiments, the reduced expression or activity level of ADCY in the subject is tissue or cell type specific. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9.

In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level.

In some embodiments, the subject of the method is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a human child.

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. In another embodiment, the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotrides-1-en-2-amine); Compounds such as 7,8-dihydro-5(6H)-quinonolinone derivatives disclosed in Japanese Patent Application No. 2001-153954 (preferably 2-amino-7-(4-chlorophenyl)-7,8-di Hydro-5(6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7 ,8-dihydro-5(6H)-quinazolinone;4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7- (2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; Cl-ANT-ATP; Cl-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; Bis-MANT-ATP; Bis-MANT-ITP; Bis-MANT-CTP; Bis-MANT-IDP; Bis-MANT-IMP; Bis-Cl-ANT-ATP; Bis-Cl-ANT-ITP; Bis-Br-ANT-ATP; Bis-Br-ANT-ITP; Bis-Pr-ANT-ATP; Bis-Pr-ANT-ITP; Bis-AcNH-ANT-ATP; Bis-AcNH-ANT-ITP; NKY80; vidarabine; 2', 5'-dd-3'-ATP; AraAde; PMC6; NB001; BODIPY-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; or a pharmaceutically acceptable salt thereof.

In some embodiments, the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylate cyclase activating polypeptide.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

The present invention further provides a method of treating or preventing ventricular systolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595 , JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828 /GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/TTAA, rs8049452/GG, rs8061182/AA, rs2238448/AA , rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA. In certain embodiments, the ventricular systolic insufficiency is left ventricular systolic insufficiency. In certain embodiments, the ventricular systolic insufficiency is right ventricular systolic insufficiency.

The present invention further provides a method of treating or preventing ventricular systolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595 , JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject /AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs It is known to have GT. In some embodiments, the subject is known to have the genotype rs1967309/AG. In certain embodiments, the ventricular systolic insufficiency is left ventricular systolic insufficiency. In certain embodiments, the ventricular systolic insufficiency is right ventricular systolic insufficiency.

The present invention also provides a method of treating or preventing ventricular systolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ -28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA , rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs2048061182/GG, rs2238448/GG, rs2238448/GG /CC, rs2531971/CC, or rs12599911/TT. In certain embodiments, the ventricular systolic insufficiency is left ventricular systolic insufficiency. In certain embodiments, the ventricular systolic insufficiency is right ventricular systolic insufficiency.

Methods for determining whether a subject has a particular genotype are well known to those skilled in the art, see eg WO 2014/154606A1 and WO 2016/016157A1.

How to reduce the risk of ventricular systolic insufficiency

The present invention relates to a method comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor. In certain embodiments, the ventricular systolic insufficiency is left ventricular systolic insufficiency. In certain embodiments, the ventricular systolic insufficiency is right ventricular systolic insufficiency.

In certain embodiments, administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. In some embodiments, each of the CETP inhibitor and ADCY inhibitor is in a separate composition. In some embodiments, the CETP inhibitor and ADCY inhibitor are present in the same composition.

The present invention provides a method of reducing the risk of ventricular systolic insufficiency comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has a reduced expression or activity level of ADCY compared to a control level. , wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor. In certain embodiments, the ventricular systolic insufficiency is left ventricular systolic insufficiency. In certain embodiments, the ventricular systolic insufficiency is right ventricular systolic insufficiency.

In certain embodiments, the control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY in a subject who does not respond positively to treatment with a CETP inhibitor in the absence of the ADCY inhibitor. In certain embodiments, the decreased expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene in the subject. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9. Methods for measuring the expression or activity level of ADCY are disclosed herein.

In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, and the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or any pharmaceutically acceptable salts.

In some embodiments, ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these .

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. In another embodiment, the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotrides-1-en-2-amine); Compounds such as 7,8-dihydro-5(6H)-quinonolinone derivatives disclosed in Japanese Patent Application No. 2001-153954 (preferably 2-amino-7-(4-chlorophenyl)-7,8-di Hydro-5(6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7 ,8-dihydro-5(6H)-quinazolinone;4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7- (2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; Cl-ANT-ATP; Cl-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; Bis-MANT-ATP; Bis-MANT-ITP; Bis-MANT-CTP; Bis-MANT-IDP; Bis-MANT-IMP; Bis-Cl-ANT-ATP; Bis-Cl-ANT-ITP; Bis-Br-ANT-ATP; Bis-Br-ANT-ITP; Bis-Pr-ANT-ATP; Bis-Pr-ANT-ITP; Bis-AcNH-ANT-ATP; Bis-AcNH-ANT-ITP; NKY80; vidarabine; 2', 5'-dd-3'-ATP; AraAde; PMC6; NB001; BODIPY-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; or a pharmaceutically acceptable salt thereof.

In some embodiments, the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylate cyclase activating polypeptide.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

The invention further provides a method of reducing the risk of ventricular systolic insufficiency comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595 , JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828 /GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/TTAA, rs8049452/GG, rs8061182/AA, rs2238448/AA , rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA. In certain embodiments, the ventricular systolic insufficiency is left ventricular systolic insufficiency. In certain embodiments, the ventricular systolic insufficiency is right ventricular systolic insufficiency.

The invention further provides a method of reducing the risk of ventricular systolic insufficiency comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595 , JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject /AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs It is known to have GT. In some embodiments, the subject is known to have the genotype rs1967309/AG. In certain embodiments, the ventricular systolic insufficiency is left ventricular systolic insufficiency. In certain embodiments, the ventricular systolic insufficiency is right ventricular systolic insufficiency.

The invention also provides a method of reducing the risk of ventricular systolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ -28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA , rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs2048061182/GG, rs2238448/GG, rs2238448/GG /CC, rs2531971/CC, or rs12599911/TT. In certain embodiments, the ventricular systolic insufficiency is left ventricular systolic insufficiency. In certain embodiments, the ventricular systolic insufficiency is right ventricular systolic insufficiency.

How to treat or prevent ventricular diastolic insufficiency

The present invention relates to a method comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor. In certain embodiments, the ventricular insufficiency is left ventricular diastolic insufficiency. In certain embodiments, the ventricular insufficiency is right ventricular diastolic insufficiency.

In certain embodiments, administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. In some embodiments, each of the CETP inhibitor and ADCY inhibitor is in a separate composition. In some embodiments, the CETP inhibitor and ADCY inhibitor are present in the same composition.

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine); 2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); 2-Amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)- Quinazolinone, 4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8 -dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; C1-ANT-ATP; C1-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; bis-MANT-ATP; bis-MANT-ITP; bis-MANT-CTP; bis-MANT-IDP; bis-MANT-IMP; bis-Cl-ANT-ATP; bis-Cl-ANT-ITP; bis-Br-ANT-ATP; bis-Br-ANT-ITP; bis-Pr-ANT-ATP; bis-Pr-ANT-ITP; bis-AcNH-ANT-ATP; bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP; araade; PMC6; NB001; Body P-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylic acid cyclase-activating polypeptide; or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

Another aspect of the invention provides a method of treating or preventing ventricular diastolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has reduced expression of ADCY compared to a control level. or activity level, wherein reduced expression or activity level of ADCY indicates that the subject will benefit from administration of the CETP inhibitor. In certain embodiments, the ventricular insufficiency is left ventricular diastolic insufficiency. In certain embodiments, the ventricular insufficiency is right ventricular diastolic insufficiency.

In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, and the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or any pharmaceutically acceptable salts.

In some embodiments, ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these .

In certain embodiments, the control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY in a subject who does not respond positively to treatment with a CETP inhibitor in the absence of the ADCY inhibitor. In certain embodiments, the decreased expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene in the subject. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9.

Activity levels of ADCY can be detected using techniques known in the art. For example, adenylate cyclase assays are described in Salomon et al., (1974) Analytical Biochemistry , 58(2): 541-548; Wiegn et al., (1993) Anal Biochem. 208(2):217-22; and Storm et al., (1998) Neuron , 20:1199-1210.

In some embodiments, the expression level of ADCY is determined at the protein expression level. In some embodiments, protein expression levels of ADCY are assayed using specific antibody and protein assays. Any suitable method or assay can be used to measure ADCY protein expression levels in a biological sample from a subject. Numerous antibody-based detection formats are well known in the art and include ELISA (enzyme linked immunosorbent assay), radioimmunoassay, immunoblot, western blot, flow cytometry, immunofluorescence assay, immunoprecipitation, protein A assay, immunoelectrophoretic assay. and other related technologies. In some embodiments, antibody binding is detected by detecting a label on the primary antibody. In other embodiments, the primary antibody is detected by detecting binding of the secondary antibody or reagent to the primary antibody. In a further embodiment, the secondary antibody is labeled. Many means for detecting binding in an immunoassay are known in the art and are within the scope of the kits, assays and methods described herein. Antibodies specific for ADCY may be provided as a diagnostic kit comprising one or more of these procedures to quantify ADCY expression. Kits may include other components, packaging, instructions or other materials to aid in protein quantification and use of the kit.

Anti-ADCY antibodies as described herein can be prepared by inoculation of appropriate animals with polypeptides or antigenic fragments, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and/or nucleic acids encoding such anti-ADCY antibodies. It can be prepared commercially or routinely according to methods such as, but not limited to, expressing recombinant cells. Immunization of animals with purified recombinant ADCY or a peptide fragment thereof is an example of a method for producing anti-ADCY antibodies. Similarly, immunization of animals with purified recombinant ADCY or peptide fragments thereof is an example of a method for making anti-ADCY antibodies.

In another embodiment, the level of ADCY is assayed at the mRNA level. For example, RT-PCR and a pair of specific primers may be used. mRNA is prepared and analyzed according to well-established protocols.

In certain embodiments, the reduced expression or activity level of ADCY in the subject is tissue or cell type specific. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9.

In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level.

In some embodiments, the subject of the method is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a human child.

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. In another embodiment, the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotrides-1-en-2-amine); Compounds such as 7,8-dihydro-5(6H)-quinonolinone derivatives disclosed in Japanese Patent Application No. 2001-153954 (preferably 2-amino-7-(4-chlorophenyl)-7,8-di Hydro-5(6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7 ,8-dihydro-5(6H)-quinazolinone;4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7- (2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; Cl-ANT-ATP; Cl-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; Bis-MANT-ATP; Bis-MANT-ITP; Bis-MANT-CTP; Bis-MANT-IDP; Bis-MANT-IMP; Bis-Cl-ANT-ATP; Bis-Cl-ANT-ITP; Bis-Br-ANT-ATP; Bis-Br-ANT-ITP; Bis-Pr-ANT-ATP; Bis-Pr-ANT-ITP; Bis-AcNH-ANT-ATP; Bis-AcNH-ANT-ITP; NKY80; vidarabine; 2', 5'-dd-3'-ATP; AraAde; PMC6; NB001; BODIPY-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; or a pharmaceutically acceptable salt thereof.

In some embodiments, the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylate cyclase activating polypeptide.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

The invention further provides a method of treating or preventing ventricular diastolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595 , JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828 /GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/TTAA, rs8049452/GG, rs8061182/AA, rs2238448/AA , rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA. In certain embodiments, the ventricular insufficiency is left ventricular diastolic insufficiency. In certain embodiments, the ventricular insufficiency is right ventricular diastolic insufficiency.

The invention further provides a method of treating or preventing ventricular diastolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595 , JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject /AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs It is known to have GT. In some embodiments, the subject is known to have the genotype rs1967309/AG. In certain embodiments, the ventricular insufficiency is left ventricular diastolic insufficiency. In certain embodiments, the ventricular insufficiency is right ventricular diastolic insufficiency.

The present invention also provides a method of treating or preventing ventricular diastolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ -28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA , rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs2048061182/GG, rs2238448/GG, rs2238448/GG /CC, rs2531971/CC, or rs12599911/TT. In certain embodiments, the ventricular insufficiency is left ventricular diastolic insufficiency. In certain embodiments, the ventricular insufficiency is right ventricular diastolic insufficiency.

Methods for determining whether a subject has a particular genotype are well known to those skilled in the art, see eg WO 2014/154606A1 and WO 2016/016157A1.

How to reduce the risk of ventricular insufficiency

The present invention relates to a method comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor. In certain embodiments, the ventricular insufficiency is left ventricular diastolic insufficiency. In certain embodiments, the ventricular insufficiency is right ventricular diastolic insufficiency.

In certain embodiments, administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. In some embodiments, each of the CETP inhibitor and ADCY inhibitor is in a separate composition. In some embodiments, the CETP inhibitor and ADCY inhibitor are present in the same composition.

The present invention provides a method of reducing the risk of ventricular diastolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has a reduced expression or activity level of ADCY compared to a control level. , wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor. In certain embodiments, the ventricular insufficiency is left ventricular diastolic insufficiency. In certain embodiments, the ventricular insufficiency is right ventricular diastolic insufficiency.

In certain embodiments, the control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY in a subject who does not respond positively to treatment with a CETP inhibitor in the absence of the ADCY inhibitor. In certain embodiments, the decreased expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene in the subject. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9. Methods for measuring the expression or activity level of ADCY are disclosed herein.

In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, and the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or any pharmaceutically acceptable salts.

In some embodiments, ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these .

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. In another embodiment, the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotrides-1-en-2-amine); Compounds such as 7,8-dihydro-5(6H)-quinonolinone derivatives disclosed in Japanese Patent Application No. 2001-153954 (preferably 2-amino-7-(4-chlorophenyl)-7,8-di Hydro-5(6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7 ,8-dihydro-5(6H)-quinazolinone;4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7- (2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; Cl-ANT-ATP; Cl-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; Bis-MANT-ATP; Bis-MANT-ITP; Bis-MANT-CTP; Bis-MANT-IDP; Bis-MANT-IMP; Bis-Cl-ANT-ATP; Bis-Cl-ANT-ITP; Bis-Br-ANT-ATP; Bis-Br-ANT-ITP; Bis-Pr-ANT-ATP; Bis-Pr-ANT-ITP; Bis-AcNH-ANT-ATP; Bis-AcNH-ANT-ITP; NKY80; vidarabine; 2', 5'-dd-3'-ATP; AraAde; PMC6; NB001; BODIPY-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; or a pharmaceutically acceptable salt thereof.

In some embodiments, the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylate cyclase activating polypeptide.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

The invention further provides a method of reducing the risk of ventricular diastolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595 , JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828 /GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/TTAA, rs8049452/GG, rs8061182/AA, rs2238448/AA , rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA. In certain embodiments, the ventricular insufficiency is left ventricular diastolic insufficiency. In certain embodiments, the ventricular insufficiency is right ventricular diastolic insufficiency.

The invention further provides a method of reducing the risk of ventricular diastolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595 , JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject /AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs It is known to have GT. In some embodiments, the subject is known to have the genotype rs1967309/AG. In certain embodiments, the ventricular insufficiency is left ventricular diastolic insufficiency. In certain embodiments, the ventricular insufficiency is right ventricular diastolic insufficiency.

The present invention also provides a method of reducing the risk of ventricular diastolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ -28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA , rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs2048061182/GG, rs2238448/GG, rs2238448/GG /CC, rs2531971/CC, or rs12599911/TT. In certain embodiments, the ventricular insufficiency is left ventricular diastolic insufficiency. In certain embodiments, the ventricular insufficiency is right ventricular diastolic insufficiency.

How to treat or prevent ejection fraction-preserving heart failure

The present invention relates to a method comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor.

In certain embodiments, administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. In some embodiments, each of the CETP inhibitor and ADCY inhibitor is in a separate composition. In some embodiments, the CETP inhibitor and ADCY inhibitor are present in the same composition.

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine); 2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); 2-Amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)- Quinazolinone, 4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8 -dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; C1-ANT-ATP; C1-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; bis-MANT-ATP; bis-MANT-ITP; bis-MANT-CTP; bis-MANT-IDP; bis-MANT-IMP; bis-Cl-ANT-ATP; bis-Cl-ANT-ITP; bis-Br-ANT-ATP; bis-Br-ANT-ITP; bis-Pr-ANT-ATP; bis-Pr-ANT-ITP; bis-AcNH-ANT-ATP; bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP; araade; PMC6; NB001; Body P-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylic acid cyclase-activating polypeptide; or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

Another aspect of the invention provides a method of treating or preventing ejection fraction-preserving heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has reduced expression of ADCY compared to a control level or activity level, wherein reduced expression or activity level of ADCY indicates that the subject will benefit from administration of the CETP inhibitor.

In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, and the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or any pharmaceutically acceptable salts.

In some embodiments, ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these .

In certain embodiments, the control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY in a subject who does not respond positively to treatment with a CETP inhibitor in the absence of the ADCY inhibitor. In certain embodiments, the decreased expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene in the subject. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9.

Activity levels of ADCY can be detected using techniques known in the art. For example, adenylate cyclase assays are described in Salomon et al., (1974) Analytical Biochemistry , 58(2): 541-548; Wiegn et al., (1993) Anal Biochem. 208(2):217-22; and Storm et al., (1998) Neuron , 20:1199-1210.

In some embodiments, the expression level of ADCY is determined at the protein expression level. In some embodiments, protein expression levels of ADCY are assayed using specific antibody and protein assays. Any suitable method or assay can be used to measure ADCY protein expression levels in a biological sample from a subject. Numerous antibody-based detection formats are well known in the art and include ELISA (enzyme linked immunosorbent assay), radioimmunoassay, immunoblot, western blot, flow cytometry, immunofluorescence assay, immunoprecipitation, protein A assay, immunoelectrophoretic assay. and other related technologies. In some embodiments, antibody binding is detected by detecting a label on the primary antibody. In other embodiments, the primary antibody is detected by detecting binding of the secondary antibody or reagent to the primary antibody. In a further embodiment, the secondary antibody is labeled. Many means for detecting binding in an immunoassay are known in the art and are within the scope of the kits, assays and methods described herein. Antibodies specific for ADCY may be provided as a diagnostic kit comprising one or more of these procedures to quantify ADCY expression. Kits may include other components, packaging, instructions or other materials to aid in protein quantification and use of the kit.

Anti-ADCY antibodies as described herein can be prepared by inoculation of appropriate animals with polypeptides or antigenic fragments, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and/or nucleic acids encoding such anti-ADCY antibodies. It can be prepared commercially or routinely according to methods such as, but not limited to, expressing recombinant cells. Immunization of animals with purified recombinant ADCY or a peptide fragment thereof is an example of a method for producing anti-ADCY antibodies. Similarly, immunization of animals with purified recombinant ADCY or peptide fragments thereof is an example of a method for making anti-ADCY antibodies.

In another embodiment, the level of ADCY is assayed at the mRNA level. For example, RT-PCR and a pair of specific primers may be used. mRNA is prepared and analyzed according to well-established protocols.

In certain embodiments, the reduced expression or activity level of ADCY in the subject is tissue or cell type specific. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9.

In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. In some embodiments, the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level.

In some embodiments, the subject of the method is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a human child.

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. In another embodiment, the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotrides-1-en-2-amine); Compounds such as 7,8-dihydro-5(6H)-quinonolinone derivatives disclosed in Japanese Patent Application No. 2001-153954 (preferably 2-amino-7-(4-chlorophenyl)-7,8-di Hydro-5(6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7 ,8-dihydro-5(6H)-quinazolinone;4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7- (2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; Cl-ANT-ATP; Cl-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; Bis-MANT-ATP; Bis-MANT-ITP; Bis-MANT-CTP; Bis-MANT-IDP; Bis-MANT-IMP; Bis-Cl-ANT-ATP; Bis-Cl-ANT-ITP; Bis-Br-ANT-ATP; Bis-Br-ANT-ITP; Bis-Pr-ANT-ATP; Bis-Pr-ANT-ITP; Bis-AcNH-ANT-ATP; Bis-AcNH-ANT-ITP; NKY80; vidarabine; 2', 5'-dd-3'-ATP; AraAde; PMC6; NB001; BODIPY-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; or a pharmaceutically acceptable salt thereof.

In some embodiments, the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylate cyclase activating polypeptide.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

The present invention also provides a method of treating or preventing heart failure with preserved ejection fraction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595 , JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828 /GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/TTAA, rs8049452/GG, rs8061182/AA, rs2238448/AA , rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

The present invention also provides a method of treating or preventing heart failure with preserved ejection fraction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595 , JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject /AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs It is known to have GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

The present invention also provides a method of treating or preventing heart failure with preserved ejection fraction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ -28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA , rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs208061182/GG, rs2238448/GG, rs2238448/GG /CC, rs2531971/CC, or rs12599911/TT.

Methods for determining whether a subject has a particular genotype are well known to those skilled in the art, see eg WO 2014/154606A1 and WO 2016/016157A1.

How to reduce the risk of heart failure with preservation of ejection fraction

The present invention relates to a method comprising: a) a CETP inhibitor; and b) administering to a subject in need thereof an effective amount of an ADCY inhibitor.

In certain embodiments, administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. In some embodiments, each of the CETP inhibitor and ADCY inhibitor is in a separate composition. In some embodiments, the CETP inhibitor and ADCY inhibitor are present in the same composition.

The present invention provides a method of reducing the risk of heart failure with preserved ejection fraction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject has a reduced expression or activity level of ADCY compared to a control level. , wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor.

In certain embodiments, the control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY in a subject who does not respond positively to treatment with a CETP inhibitor in the absence of the ADCY inhibitor. In certain embodiments, the decreased expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene in the subject. In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10. In some embodiments, ADCY is ADCY9. Methods for measuring the expression or activity level of ADCY are disclosed herein.

In some embodiments, ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, and the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or any pharmaceutically acceptable salts.

In some embodiments, ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these .

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. In another embodiment, the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. In certain embodiments, the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'-monophosphate; MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotrides-1-en-2-amine); Compounds such as 7,8-dihydro-5(6H)-quinonolinone derivatives disclosed in Japanese Patent Application No. 2001-153954 (preferably 2-amino-7-(4-chlorophenyl)-7,8-di Hydro-5(6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7 ,8-dihydro-5(6H)-quinazolinone;4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7- (2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; Cl-ANT-ATP; Cl-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; Bis-MANT-ATP; Bis-MANT-ITP; Bis-MANT-CTP; Bis-MANT-IDP; Bis-MANT-IMP; Bis-Cl-ANT-ATP; Bis-Cl-ANT-ITP; Bis-Br-ANT-ATP; Bis-Br-ANT-ITP; Bis-Pr-ANT-ATP; Bis-Pr-ANT-ITP; Bis-AcNH-ANT-ATP; Bis-AcNH-ANT-ITP; NKY80; vidarabine; 2', 5'-dd-3'-ATP; AraAde; PMC6; NB001; BODIPY-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; or a pharmaceutically acceptable salt thereof.

In some embodiments, the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylate cyclase activating polypeptide.

In certain embodiments, the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

In certain embodiments, the subject has genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs373011967/GA GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

In certain embodiments, the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/AA, rs2283497/AA CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.

The invention further provides a method of reducing the risk of heart failure with preserved ejection fraction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595 , JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828 /GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/TTAA, rs8049452/GG, rs8061182/AA, rs2238448/AA , rs12920508/GG, rs2531971/AA, or rs12599911/GG. In some embodiments, the subject is known to have the genotype rs1967309/AA.

The invention further provides a method of reducing the risk of heart failure with preserved ejection fraction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595 , JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject /AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs It is known to have GT. In some embodiments, the subject is known to have the genotype rs1967309/AG.

The invention also provides a method of reducing the risk of heart failure with preserved ejection fraction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ -28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of these, wherein the subject has genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/ AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/GG It is known to have rs12920508/CC, rs2531971/CC, or rs12599911/TT.

Dosage

The dosage of the CETP inhibitor and ADCY inhibitor of the methods and compositions of the present invention will depend on the type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated or prevented; severity of cardiovascular events; route of administration; kidney or liver function of the subject; or the CETP or ADCY inhibitor to be administered.

In some embodiments, the daily dosage of a CETP inhibitor useful in the methods and compositions of the present invention ranges from about 1 mg to about 1000 mg.

In some embodiments, the daily dosage of ADCY inhibitors useful in the methods and compositions of the present invention ranges from about 1 mg to about 1000 mg.

In certain embodiments, the CETP inhibitor is dalcetrapib or a pharmaceutically acceptable salt thereof, wherein dalcetrapib or a pharmaceutically acceptable salt thereof is administered daily at about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg; It is administered orally in an amount of 900 mg, or 1000 mg.

In certain embodiments, the CETP inhibitor is torcetrapib or a pharmaceutically acceptable salt thereof, wherein torcetrapib or a pharmaceutically acceptable salt thereof is administered daily at about 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg; It is administered orally in an amount of 90 mg or 100 mg.

In certain embodiments, the CETP inhibitor is anacetrapib or a pharmaceutically acceptable salt thereof, wherein anacetrapib or a pharmaceutically acceptable salt thereof is administered daily at about 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg; It is administered orally in an amount of 180 mg or 200 mg.

In certain embodiments, the CETP inhibitor is evacetrapib or a pharmaceutically acceptable salt thereof, wherein the evacetrapib or a pharmaceutically acceptable salt thereof is administered at about 30 mg, 60 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg daily. , 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg or 600mg.

In certain embodiments, the CETP inhibitor is BAY 60-5521 or a pharmaceutically acceptable salt thereof, wherein BAY 60-5521 or a pharmaceutically acceptable salt thereof is about 5 mg, 12.5 mg, 25 mg, 30 mg, 40 mg, 50 mg daily , 60 mg, 70 mg, 80 mg, 90 mg or 100 mg orally.

In some embodiments, the subject of the method is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a human child.

Compositions and kits

The present invention also relates to a pharmaceutical composition comprising (a) an effective amount of a CETP inhibitor and an ADCY inhibitor; and (b) a pharmaceutically acceptable carrier or vehicle.

In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these.

In certain embodiments, the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.

In certain embodiments, the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine), 2',5'-dideoxyadenosine, 9-cyclopentyladenine, 2',5'-dide Oxyadenosine 3'-diphosphate, 2',5'-dideoxyadenosine 3'-monophosphate, MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotride-1-en-2- amine), compounds such as 7,8-dihydro-5(6H)-quinonolinone derivatives disclosed in Japanese Patent Application No. 2001-153954 (preferably 2-amino-7-(4-chlorophenyl)-7; 8-Dihydro-5(6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7- Phenyl-7,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2- amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP; 3'-MANT-2'dATP; MANT-ATPγS; MANT-ITPγS; MANT-GTPγS; MANT-UTPγS; ANT-ATP; Cl-ANT-ATP; Cl-ANT-ITP; Br-ANT-ITP; Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; Bis-MANT-ATP; Bis-MANT-ITP; Bis-MANT-CTP; Bis-MANT-IDP; Bis-MANT-IMP; Bis-Cl-ANT-ATP; Bis-Cl-ANT-ITP; Bis-Br-ANT-ATP; Bis-Br-ANT-ITP; Bis-Pr-ANT-ATP; Bis-Pr-ANT-ITP; Bis-AcNH-ANT-ATP; Bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP; AraAde; PMC6; NB001; BODIPY-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide; SB-268262; LRE1; 2',5'-dideoxyadenosine; or 2',5'-dideoxyadenosine 3'-triphosphate tetrasodium salt; or a pharmaceutically acceptable salt thereof.

In certain embodiments, the pharmaceutically acceptable carrier or vehicle may be water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as liquids such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. The pharmaceutical excipient may be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. Also useful are adjuvants, stabilizers, thickeners, lubricants and colorants. In one embodiment, the pharmaceutically acceptable excipient when administered to a subject is sterile. Water is a useful excipient when the CETP inhibitor or ADCY inhibitor is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid excipients, particularly solutions for injection. Suitable pharmaceutical excipients are also starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dry skim milk, glycerol, propylene, glycol, water. , ethanol, and the like. If desired, the composition may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

Compositions may be specifically formulated for administration in solid or liquid form, including those suitable for: (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g. eg, those targeted for buccal, sublingual and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, eg, by subcutaneous, intramuscular, intravenous or epidural injection, eg, as a sterile solution or suspension, or as a sustained release preparation; (3) topical application, eg, as a cream, ointment, or controlled release patch or spray applied to the skin; (4) vaginal or rectal, for example as a pessary, cream or foam; (5) sublingual; (6) eyeball; (7) transdermal; or (8) nasal.

Compositions of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of 100%, this amount will range from about 0.1% to about 99% of the active ingredient, for example from about 5% to about 70%, or from about 10% to about 30%.

In certain embodiments, the composition of the present invention comprises an excipient selected from the group consisting of cyclodextrins, cellulose, liposomes, micellar formers, such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides; and CETP inhibitors or ADCY inhibitors. In certain embodiments, the composition makes the CETP inhibitor or ADCY inhibitor orally bioavailable.

Such compositions or methods of making the compositions comprise the step of bringing into association a CETP inhibitor or ADCY inhibitor with a carrier and optionally one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the CETP inhibitor or ADCY inhibitor with a liquid carrier, or finely divided solid carrier, or both, and then, if necessary, shaping the product.

Compositions of the present invention suitable for oral administration include capsules, cachets, pills, tablets, lozenges (flavored based, usually with sucrose and acacia or tragacanth), powders, granules, or solutions or suspensions of aqueous or non-aqueous liquids. or in the form of oil-in-water or water-in-oil liquid emulsions, elixirs or syrups or pills (using an inert base such as gelatin and glycerin, or sucrose and acacia) and/or mouthwash, each with a predetermined amount of CETP as the active ingredient. inhibitors or ADCY inhibitors. The CETP inhibitor or ADCY inhibitor may also be administered as a bolus, ointment or paste.

In the solid dosage forms of the present invention (capsules, tablets, pills, dragees, powders, granules, truche, etc.) for oral administration, the active ingredient is sodium citrate or dicalcium phosphate and/or one or more pharmaceuticals such as any of can be mixed with acceptable carriers as: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants such as glycerol; (4) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retardants such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds and surfactants such as poloxamers and sodium lauryl sulfate; (7) wetting agents such as cetyl alcohol, glycerol monostearate and non-ionic surfactants; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid and mixtures thereof; (10) colorants; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical composition may also include a buffer. Solid compositions of a similar type may also be used as fillers in soft and hard shell gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets contain binders (e.g., gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface active or dispersing agents. It can be prepared using Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may also be formulated to provide slow or controlled release of the active ingredient therein using hydroxypropylmethyl cellulose in various proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, eg, freeze-drying. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately prior to use. These compositions may also optionally contain opacifying agents and they may release the active ingredient(s) alone or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric materials and waxes. The active ingredient may also be in microencapsulated form, if appropriate with one or more of the above excipients.

Liquid formulations for oral administration of a CETP inhibitor or ADCY inhibitor include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid formulations may contain, for example, water or ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed). , peanut, corn, germ, olive, castor and sesame oil), glycerol, tetrahydrofuryl alcohol, fatty acid esters of polyethylene glycol and sorbitan, and other solvents such as mixtures thereof, solubilizers and emulsifiers, as commonly used in the art. may contain inert diluents used.

Besides inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

In addition to the active compound, suspensions may be prepared, for example, with ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth and mixtures thereof may contain the same suspending agent.

Compositions of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be presented as suppositories, which contain one or both of a CETP inhibitor and an ADCY inhibitor, for example cocoa butter, polyethylene glycol, suppository wax or salicylate. and may be prepared by admixture with one or more suitable non-irritating excipients or carriers that are solid at room temperature but liquid at body temperature, which will dissolve in the rectum or vaginal cavity to release the active compound.

Compositions of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray compositions containing carriers known in the art to be suitable.

Formulations for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be admixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants as may be required.

Ointments, pastes, creams and gels, in addition to the active compounds of the present invention, include animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide. , or mixtures thereof.

Powders and sprays may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Transdermal patches have the added advantage of providing controlled delivery of a CETP inhibitor or ADCY inhibitor to a subject. Such formulations can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate of this flow can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Pharmaceutical compositions of the present invention suitable for parenteral administration include a CETP inhibitor, an ADCY inhibitor and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile injectable solutions or dispersions immediately prior to use. may contain a sterile powder that may be reconstituted as a sterile powder, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes or suspending or thickening agents that render the composition isotonic with the blood of the intended recipient.

Examples of suitable aqueous and non-aqueous carriers that may be used in the compositions of the present invention include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, ethyl Injectable organic esters such as oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin or, in the case of dispersions, by maintaining the required particle size and by using surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying and dispersing agents. Prevention of the action of microorganisms on the subject composition can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenolsorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the composition. Prolonged absorption of the injectable pharmaceutical form can also be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of poorly water soluble crystalline or amorphous material. The rate of absorption of a drug depends on the rate of dissolution, which may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are prepared by forming microcapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable compositions can also be prepared by entrapping the drug in liposomes or microemulsions suitable for body tissues.

When CETP inhibitors or ADCY inhibitors are administered to humans and animals as medicaments, they, by themselves or in combination with a pharmaceutically acceptable carrier, for example 0.1 to 99% (more preferably 10 to 30%) of the active ingredient It can be provided as a pharmaceutical composition containing.

The formulations of the present invention may be administered orally, parenterally, topically or rectally. These are, of course, provided in a form suitable for each route of administration. For example, they may be in tablet or capsule form by injection, inhalation, eye lotion, ointment, suppository, and the like; administration by injection, infusion or inhalation; topical as a lotion or ointment; and rectally by suppository. Oral administration is preferred.

As used herein, the phrases "parenterally administered" and "administered parenterally" refer to modes of administration other than enteral and topical administration, generally by injection, intravenously, intramuscularly, intraarterially, intrathecally, capsularly. Intra-orbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcutaneous, intra-articular, subcapsular, subarachnoid, intrathecal, and intrasternal injections and infusions are included without limitation.

As used herein, the phrases "systemic administration", "administered systemically", "peripheral administration" and "administered peripherally" refer to the administration of a compound, drug or other substance other than directly into the central nervous system, wherein the patient enters the system of the body, and thus is administered subcutaneously, for example in metabolic and other similar processes.

These compounds can be administered to humans for treatment by any suitable route of administration, including, for example, spray, rectal, vaginal, parenteral, oral by intracisternal, nasal and topical by drops, including powders, ointments or buccal and sublingual. and other animals.

Irrespective of the route of administration selected, the CETP inhibitor or ADCY inhibitor, which may be used in a suitable hydrated form, and/or the pharmaceutical composition of the present invention is formulated into a pharmaceutically acceptable dosage form by conventional methods known to those skilled in the art.

Actual dosage levels of the active ingredient in the compositions of the present invention may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration that is not toxic to the patient.

The selected dosage level will depend on the activity of the particular CETP inhibitor or ADCY inhibitor, or ester, salt or amide thereof, used, route of administration, time of administration, rate of excretion or metabolism, rate and extent of absorption of the particular compound employed, duration of treatment, It will depend on a variety of factors including other drugs, compounds and/or materials used with the particular compound, age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical arts. .

A physician or veterinarian can readily determine and prescribe an effective amount of the pharmaceutical composition. For example, a physician or veterinarian may start a dose of a CETP inhibitor or ADCY inhibitor used in a pharmaceutical composition at a level lower than necessary to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. can

In some embodiments, a suitable daily dose of a CETP inhibitor or ADCY inhibitor is the amount of the CETP inhibitor or ADCY inhibitor that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above.

If desired, the effective daily dose of the CETP inhibitor or antidiabetic agent will be 2, 3, 4, 5, 6 or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage form, e.g., per day. It may be administered once.

The present invention also provides kits useful for treating or preventing cardiovascular conditions or reducing the risk of cardiovascular events as described herein. In some embodiments, the kit comprises a CETP inhibitor or ADCY inhibitor and instructions for use thereof. In some embodiments, each of the CETP inhibitor and ADCY inhibitor is in separate compositions. In some embodiments, the CETP inhibitor and ADCY inhibitor are present in the same composition. The present invention also provides a CETP inhibitor and ADCY inhibitor as described herein, and a composition comprising an effective amount of a CETP inhibitor and ADCY inhibitor as described herein for use in the methods described herein.

Example

Example 1: Adyc9 Generation of Gene Capture Mice

Adyc9 gene capture ( Adcy9 ^Gt/Gt ) mice were initially generated from Lexicon Pharmaceuticals (Zambrowicz et al., Proc Natl Acad Sci US A. (2003) 100:14109-14). Cryopreserved sperm of the B6;129S5- ^{Adcy9 Gt(neo)159Lex} /Mmucd strain were imported from the Mutant Mouse Regional Resource Center (MMRRC) for in vitro fertilization and fallopian tube transplantation at the Institute of Immune Cancer Research (IRIC) animal facility in a specific pathogen-free region. Their rearing and breeding were approved by the University de Montreal Deontology Committee on Animal Testing. MaxBax accelerated backcrossing and genotyping (Charles River, Sherbrooke, Canada) was performed to achieve >98.6% C57BL/6J genetic background. Procedures involving mice were performed at the Montreal Heart Institute (MHI) Research Center and were approved by the Regional Ethics Committee for Animal Research in accordance with the Canadian Animal Care Guidelines. Adcy9 ^Gt/Gt mice were bred by crossing Adcy9 ^Wt/Gt Adcy9WT/Gt animals. Mice hemizygous for the transgenic human CETP minigene (CETP ^WT ) were obtained from Jackson Laboratories (Bar Harbor, ME) and were in a 100% C57BL/6J genetic background. To obtain mice transfected for CETP and with homozygous inactivation for Adcy9 ^{(CETP Gt ), CETP WT} mice were first crossed with Adcy9 ^Wt/Gt animals and then transferred to mice transfected for CETP and Adcy9 ^Wt/Gt . Heterozygous for Adcy9 ^Gt/Gt or Adcy9 ^Wt/Gt animals were crossed. All mice were male under C57BL/6J background and were between 8 and 12 weeks of age. After 4 hours of fasting, blood collection was performed.

Example 2: Atherosclerosis model

Wild-type (WT) and Adcy9 ^Gt/Gt male mice (8-12 weeks old) were injected with a single dose of AAV8 viral vector expressing gain-of-function Pcsk9 ^D377Y (AAV8- Pcsk9 ^D377Y , 6.5x10 ^{11 gene copies) as previously described.} did. (Roche-Molina et al., Arterioscler Thromb Vasc Biol. (2015) 35:50-59) In a preliminary experiment to confirm the effect of AAV8-Pcsk9 ^D377Y infection on LDL receptor expression, the control group was injected with a saline solution. Starting 1 week after AAV8- Pcsk9 ^D377Y injection, mice were chow-based (Purina 5015) enriched in 0.75% cholesterol and having the following caloric composition: 20.4% protein, 42.7% carbohydrate, and 36.9% fat (3.9 kcal/g). An atherosclerotic diet (TD, 150545, Envigo, Madison, WI) was fed for 16 weeks. Food and water were freely available. After sacrifice, an experienced observer who did not see the mouse genotype investigated the development of atherosclerosis in the entire aorta, aortic root, and brachial artery.

Example 3: Adcy9 Inactivation protects against atherosclerosis

Quantification of Adcy9 mRNA expression by reverse transcription-quantitative PCR (RT-qPCR)

Mouse total RNA was extracted from the cardiac ventricles using the RNeasy Isolation Kit (QIAGEN, Toronto, ON, Canada) with a DNase I procedure according to the manufacturer's protocol. cDNA was synthesized using ^{MultiScribe™} reverse transcriptase according to the manufacturer's procedures and components of the inhibitor-free high-dose cDNA reverse transcription kit (Applied Biosystems #4368814, Foster City, CA). RNA quantification and quality was assessed using the Agilent RNA 6000 Nano Kit (Agilent Technologies, Santa Clara, CA) for the Bioanalyzer 2100 system. Primers for Adcy9 were designed using Beacon Designer software v.8 (Premier Biosoft) and obtained from IDT (Coralville, IA). Gapdh was used as a reference gene for normalization. Quantitative PCR (qPCR) was performed with SYBR-Green reaction mixture (BioRad, Hercules, CA). The qPCR conditions consisted of 40 cycles of amplification after initial denaturation at 95°C for 3 min, each cycle consisting of 10 s at 95°C and 30 s at 60°C.

The effect of the Adcy9 ^Gt modified target locus on Adcy9 ^{expression in Adcy9 Gt/Gt} mice was characterized. Using RT-qPCR, it was demonstrated that Adcy9 mRNA expression in the heart was reduced by 50% in Adcy9 ^WT/Gt mice and at least 90% in Adcy9 ^Gt/Gt mice compared to WT ( FIG. 1A ). In skeletal muscle, which was reported to have high ADCY9 gene expression, it was observed that protein expression was lost in Adcy9 ^{Gt/Gt mice compared to WT ( FIG. 1E ).} Then, WT and Adcy9 ^Gt/Gt mice were infected with AAV8- Pcsk9 ^D377Y to induce hypercholesterolemia. One week after infection, plasma PCSK9 concentrations before initiation of an atherogenic diet increased rapidly from 0.1 g/mL to 17.9 ± 3.5 g/mL in WT and to 26.6 ± 7.5 g/mL in Adcy9 ^{Gt/Gt mice.} PCSK9 concentration increased to 71.0±19.1 μg/mL in WT and 90.8±20.1 μg/mL in Adcy9 ^Gt/Gt mice after 8 weeks of atherosclerotic diet, and remained almost stable at 12 weeks (Fig. 1b). PCSK9 ^D377Y induced a similar 90% reduction in hepatic LDL receptor expression in WT and Adcy9 ^{Gt/Gt (Fig. 1c).}

Determination of Plasma Cholesterol Concentration, Lipoprotein Profile and Plasma PCSK9

Blood samples were collected in EDTA coated tubes and plasma was separated by centrifugation (2000 x g, 10 min) and stored at -80°C until analysis. Total cholesterol was quantified by a colorimetric enzyme assay (Wako Diagnostics, 999-02601, Richmond, VA) and measured at 600 nm in flat-bottomed 96-well black microplates according to the micromethod used in our laboratory. Blood samples were collected from 5 mice per group to determine the lipoprotein profile and fast protein liquid chromatography (FPLC) size fractionation on Sepharose was performed at the Specialty Liposomes Core Facility (University of Alberta, Edmonton, AB). The plasma PCSK9 concentration was determined using an ELISA kit targeting mouse PCSK9 (Cyclex Co, #CY-8078, Japan).

Plasma cholesterol levels rose at 16 weeks from 3.8±0.3 mM in WT and ^{4.9±0.2 mM in Adcy9 Gt/Gt} to 44.5±6.7 mM and 42.4±5.1 mM (P=NS) ( FIG. 1D ). Visualization of lipoprotein profiles by chromatography showed that WT and Adcy9 ^Gt/Gt mice had similar profiles enriched in HDL at baseline. PCSK9 ^D377Y and a hypercholesterolemic diet induced atherosclerotic redistribution of cholesterol from HDL particles to VLDL and LDL particles in both types of mice ( FIGS. 2A and 2B ).

En face quantification of aortic atherosclerotic lesions

Atherosclerotic lesions were quantified in whole aorta incised from the front. The aorta was fixed in 4% paraformaldehyde (PFA) overnight, then stained with a 0.7% solution of Oil Red O (Sigma-Aldrich) for 1 hour, and then counterstained with 0.05% Nuclear Fast Green (Sigma-Aldrich, F7258). Contrast is optimized. Images were captured using a Leica Microsystem (Concord, ON, Canada) stereo microscope with a digital camera (MC170 HD, Leica Microsystem). Atherosclerotic lesions were quantified from the aortic root to the iliac artery bifurcation using Image-Pro Premier 9.2 (Media Cybernetics, Inc, Rockville, MD). Percentage of atherosclerotic lesion area was expressed as a percentage of intimal area showing Oil Red O staining.

Cross-section quantification of atherosclerotic lesions in the aortic root.

The base of the heart was embedded in OCT compound, sliced into 10 μm sections, fixed with 10% cold formalin for 5 minutes, and rinsed twice with deionized water. Slides were immersed twice in 100% propylene glycol for 5 min. Aortic roots were stained with 0.7% Oil Red O solution at room temperature for 48 hours. The slides were then continuously immersed in a bath of 100% propylene glycol, 85% propylene glycol and deionized water with stirring. Slides were counterstained with hematoxylin solution for a few seconds, rinsed and mounted using aqueous medium. Atherosclerotic lesions were quantified at a constant distance from the base of the aortic sinus to 500 μm distal to the root of the aorta. Images were obtained microscopically and quantified with Image-Pro Premier 9.2.

Quantification of atherosclerotic lesions in the brachial artery

The presence of plaque, fibrin, red blood cells and breakage of the plaque cap were determined in the brachial artery. All solutions used for staining were from EMS (Hatfield, PA) with the exception of phosphotungstic acid from Sigma-Aldrich. Six micrometer-thick sections (6 μm) taken from paraffin-embedded brachial artery were modified as previously described and stained according to Carstairs' method ¹² . After rehydration, the sections are incubated in 5% ferric ammonium sulfate solution for 5 min and rinsed with tap water. The sections are then stained with Mayer's hematoxylin solution for 5 min and rinsed with tap water. Additional staining was performed with Ponso-Puccicin for 5 minutes with Orange Picric acid G for 1 hour before rinsing with distilled water for each stain. Muscle tissue was distinguished from other structures with 1% phosphotungstic acid for 3 min before rinsing with distilled water. Final staining for collagen was performed with aniline blue (2.5%, 2 min) prior to dehydration with xylene and mounting on a permount (Thermo Fisher Scientific, Toronto, ON, Canada). Sections were scored for the presence of plaque, fibrin deposition on the plaque surface and within the plaque, and breakage of the plaque cap. To obtain a positive score, it is necessary for the mouse to display the feature of interest in two sections separated by 48 μm. Plaque size was scored according to the percentage of cross-sectional area occupied by the plaques (scores of 0: <50%, 1: 50-75% and 2: >75%).

At sacrifice, the aorta exhibited an 11.3±2.1% (P<0.01, FIGS. 3A and 3D ), 65% reduction of the intimal surface covered with atherosclerotic lesions in WT mice compared to 3.8±0.6% in ^{Adcy9 Gt/Gt mice.} indicated. Cross-sectional quantification revealed a numerical reduction in plaque area along the entire aortic root by Adcy9 inactivation (p=0.07 at 500 μm, FIGS. 3B and 3E ). The brachial artery is an area in mice where plaques are more complex and prone to rupture (Rosenfeld et al., Arterioscler Thromb Vasc Biol. (2000) 20:2587-92); Figure 3c showed that all WT animals had plaques in the brachial artery, in contrast to Adcy9 ^{Gt/Gt mice (100%, vs. 50%, P<0.05).} Plaques of WT mice were also larger and exhibited more frequent fibrin deposits (P<0.05) and cap rupture on the surface compared to Adcy9 ^Gt/Gt mice ( FIG. 3F ).

Example 4: Adcy9 Inactivation reduces CD68-positive macrophages (foam cells) accumulation and their proliferation in atherosclerotic lesions

Immunofluorescence detection of CD68-positive macrophages (foam cells) and proliferation in aortic roots ( FIGS. 4A and 4D )

The base of the heart was embedded in OCT compound and 10 μm sections were cut with a cryostat. The slides were incubated in PBS to remove OCT and then immersed in 4% PFA (pH 7.4) for 20 min. After fixation, the slides were washed with PBS. Permeabilization, blocking and antibody incubation were performed in Tris solution (in mM): Tris-base 50, NaCl 150, BSA 1%, Triton X-100 0.4% and fetal bovine serum 20% (pH 7.4). The murine antibody to CD68 was diluted 1/200 (BioRad, #MCA19557) and the rabbit antibody to Ki67 was used at 1 μg/mL (Abcam, #ab15580). To determine CD68-positive cell accumulation in atherosclerotic lesions, CD68 was visualized using a goat anti-mouse antibody labeled with Alexa-647 (Thermo Fisher Scientific, # cat A-21247). For co-staining with Ki67, CD68 was visualized with a goat anti-mouse antibody labeled with Alexa-568 (Thermo Fisher Scientific, #A11077) and Ki67 was labeled with Alexa-647 (Thermo Fisher Scientific, #A-27040). CD68 was visualized using a goat anti-mouse antibody. Nuclei were counterstained with DAPI. Images were acquired with a confocal microscope (LSM 710, Zeiss, Peabody, CA). Imaging quantification was performed on three sections of the aortic root using Image-Pro Premier 9.2. The accumulation of CD68-positive foam cells was quantified as a percentage of the total lesion area in the three aortic root sections. Cells were considered positive for Ki67 if staining co-localized with DAPI. To assess proliferation of CD68-positive foam cells, double positive Ki67/CD68 cells were counted.

CD68-positive foam cells, a major component of atherosclerotic plaques, represented 19.0±1.9% and 11.4±2.1% of the lesion area in WT and Adcy9 ^{Gt/Gt mice, respectively (P<0.05, Fig. 4a).}

In situ hybridization revealed Adcy9 expression in atherosclerotic lesions at the site of foam cell accumulation (Fig. 4b). In situ hybridization was performed according to the manufacturer's recommended procedure (Advanced Cell diagnostic, Hayward, CA). Staining was performed on 6 μm thick sections of paraffin-embedded femoral artery or aortic root. Sections were counterstained with hematoxylin. It was observed that the signal for Adcy9 ^{was specific by comparing tissue sections of Adcy9 Gt/Gt} and WT mice (data not shown). The Adcy9 probe was Mm- Adcy9 targeting nucleotides 1522-2502 of NM_009624.3. A probe for the bacterial gene dapB was used as a negative control.

Immunofluorescence detection of Ki67 showed that proliferation of CD68-positive foam cells was significantly reduced in Adcy9 ^Gt/Gt compared to WT (P<0.05, FIGS. 4c and 4e ).

Example 5: Adcy9 Inactivation enhances endothelial function

In untreated animals (AAV8- Pcsk9 ^D377Y and no atherosclerotic diet), endothelial-dependent vasodilation for ACh was enhanced in the femoral arteries of Adcy9 ^Gt/Gt mice compared to WT (P<0.01, FIG. 5A ); In contrast, endothelium-independent vasodilation for nitric oxide donor SNPs was similar in both groups ( FIG. 5E ). Adcy9 inactivation also potentiated endothelium-dependent vasodilation in response to ^{increased shear stress (15 dynes/cm 2} ) compared to WT (42.3±7.1% vs. 28.2±6.3%, P=0.08, FIG. 5B ). No differences were detected between untreated mice (AAV8- Pcsk9 ^{D377Y and no atherosclerotic diet) when the aorta was assessed.} Both endothelium-dependent (ACh-induced) and endothelium-independent vasodilation were increased in Adcy9 ^Gt/Gt mice compared to WT in the femoral arteries of atherosclerotic animals (AAV8- Pcsk9 ^{D377Y and atherosclerotic diet) (P<<} 0.05, FIGS. 5c and 5f). This suggests that the sensitivity of vascular smooth muscle cells to NO may be increased by Adcy9 inactivation. A similar benefit was observed in the aorta of animals treated with AAV8-Pcsk9 ^{D377Y and an atherosclerotic diet when Adcy9 Gt/Gt} was compared to WT mice ( FIGS. 5D and 5G ).

Selective pharmacological blockade of the signaling pathway responsible for endothelial-dependent vasodilation (Vanhoutte et al., Acta Physiol (Oxf). (2017) 219:22-96) is the mechanism responsible for the improvement observed in Adcy9 ^{Gt/Gt mice.} was used to check The nitric oxide synthase blocker L-NNA significantly inhibited ACh-induced vasodilation in both WT and Adcy9 ^Gt/Gt mice (P<0.01), but flow-mediated vasodilation was numerically reduced only in Adcy9 ^{Gt/Gt mice.} (FIGS. 6A and 6D). In contrast, the cyclooxygenase (responsible for prostacyclin production) blockers meclofenamate or a cocktail of endothelial-dependent hyperpolarization blockers (TRAM-34 and apamine ) inhibited ACh-induced endothelial-dependent vasodilation in ^{Adcy9 Gt/Gt mice.} (P<0.01 for both pathways, FIGS. 6B and 6E ) but not in WT mice. Overall, these pharmacological results demonstrate that the effect of Adcy9 inactivation on endothelial function is dependent on all three endothelial cell signaling pathways.

Adcy9 ^Gt/Gt mice are systemically inactivated for Adcy9 , making it difficult to ascertain a role in vascular tissue that may be associated with the observed enhanced endothelial function. Therefore, Adcy9 mRNA expression was studied by in situ hybridization in histological sections and demonstrated in the femoral artery wall. The specificity of the Adcy9 mRNA signal was confirmed by the absence of a dot with a negative control probe (Fig. 6c).

Example 6: Adcy9 Inactivation increases body weight and adipose tissue volume

Body weight was measured every week from the week infected with AAV8- Pcsk9 ^{D377Y for a total of 16 weeks.} Feed efficiency, which is the ratio of weight gain and caloric intake (g/100 kcal), was calculated for a total of 8 weeks during the atherosclerotic diet.

Adcy9 ^Gt/Gt mice gained more body weight than WT animals during 16 weeks of atherosclerotic diet, reaching body weights of 45.1±2.4 g and 33.5±1.2 g, respectively (P<0.01, FIG. 7a ). MRI performed at week 14 showed that Adcy9 ^Gt/Gt mice showed more adipose tissue than WT (Fig. 7b), and Adcy9 ^Gt/Gt mice (9.4±1.2 cm ³ ) compared to WT (4.3±0.4 cm ³ , P< 0.01, showing twice the total body adipose tissue volume compared to Fig. 7c). This increase was confirmed by larger groin, perirenal, epididymal and interscapular fat stores (Fig. 7d). Histological sections showed that Adcy9 inactivation resulted in hypertrophic adipocytes in epididymal white adipose tissue and larger lipid droplets in scapular interscapular brown adipose tissue ( FIGS. 7E and 7F ). No significant changes in blood glucose or insulin concentrations were observed in response to an atherosclerotic diet and increased fat accumulation, suggesting that weight gain in response to Adcy9 inactivation did not alter insulin sensitivity (data not shown). not).

Example 7: Adcy9 Inactivation modulates autonomic nervous system activity

Telemetry for ECG recording

ECGs were monitored and recorded in consciously freely moving unanesthetized WT and Adcy9 ^{Gt/Gt mice using telemetry.} Mice were equipped with mouse ECG transmitters (ETA-F10, DSI, St Paul, MN) and electrodes were placed subcutaneously in the abdomen in the conventional lead II position (Brouillette et al., J Mol Cell Cardiol . (2007) 43 :159-67). Recordings were performed continuously at 1 KHz per channel using IOX (version 2.8.0.17, EMKA Inc) 10 days after surgery. ECG was determined by Thireau et al . ( Ex Physiol. (2008) 93:83-94) was analyzed for heart rate variability (HRV) using the software ECG Auto (version v3.3.0.25, EMKA Inc). Periods containing 1500 bits were analyzed for daytime (6am-6pm) and nighttime (6pm-6am). The data were analyzed to extract the time domain parameters RR interval and pNN(6), the latter representing the percentage of RR intervals that exceeded the previous interval by more than 6 ms, reflecting parasympathetic activity.

Given the difference in body weight gain between Adcy9 ^Gt/Gt and WT mice, feed efficiency, defined as the ratio of body weight gain to energy intake, was evaluated over the same time period. By atherosclerotic diet, Adcy9 ^Gt/Gt mice showed a significant increase in feed efficiency (1.2±0.1 g/100 kCal) compared to WT (0.6±0.1 g/100 kCal, P<0.01, FIG. 8a). This indicates that the autonomic nervous system-dependent control of energy balance is modified by Adcy9 inactivation. Therefore, autonomic activity was assessed by measuring heart rate variability by telemetry in WT and Adcy9 ^{Gt/Gt mice.} The RR interval was increased in Adcy9 ^Gt/Gt mice (135±5 ms) compared to WT mice (123±4 ms, P=0.05, FIG. 8b). Nocturnal heart rate was lower in Adcy9 ^Gt/Gt mice (447±10 bpm) compared to WT mice (475±10 bpm, P=0.06). pNN(6) representing the percentage of RR intervals that exceeded the previous interval by more than 6 ms ^{and reflecting parasympathetic nervous system activity 17} showed that Adcy9 ^Gt/Gt mice (21.6±2.4%) compared to WT (14.5±2.2%, P<0.05, FIG. 8c). ) increased during the night period.

Example 8: In mice expressing CETP Adcy9 Inactivation-induced atherosclerosis protection is lost.

To study the interaction between Adcy9 and CETP expression, transgenic mice for the human CETP minigene ^{(CETP WT ) were crossed with Adcy9 Gt/Gt} mice to obtain CETP and inactivated Adcy9 (CETP ^Gt ) mice. got it Two types of mice (CETP ^WT and CETP ^Gt ) received the previously described atherosclerotic protocol (including AAV8- Pcsk9 ^D377Y injection and an atherosclerotic diet). CETP ^WT and CETP ^Gt mice developed similar atherosclerotic lesions covering 11.8±1.8% and 8.6±1.9% of the intimal area, respectively (P=NS, FIGS. 9A and 9C ). 9B compares the percentage of total aortic lesion area in WT, Adcy9 ^Gt/Gt , CETP ^WT and CETP ^Gt , highlighting the absence of atherosclerotic protection in CETPGt mice compared to Adcy9 ^{Gt/Gt mice (P<0.05).} . These results indicate that Adcy9 does not significantly affect the pathogenesis of atherosclerosis in the presence of CETP.

Example 9: Adcy9 Inactivation-induced endothelial function protection is lost in mice expressing CETP

Given the loss of Adcy9 inactivation-induced atherosclerotic protection when the CETP gene is introduced, vasodilation to ACh and SNP in the femoral artery from ^{atherosclerotic CETP WT} and CETP ^{Gt was studied ( FIGS. 10A and 10B ).} . Adcy9 inactivation no longer altered endothelium-dependent vasodilation in response to ACh in the presence of CETP (Fig. 10a). However, SNP-induced vasodilation remained enhanced by Adcy9 ^{inactivation in CETP-bearing mice (P<0.01 for CETP Gt} versus CETP ^WT , FIG. 10B ). These results suggest that the atherosclerotic protective effect of Adcy9 inactivation in the absence of CETP is related to a role in endothelial function regulation.

Example 10: Body weight and adipose tissue volume Adcy9 The inactivation-induced increase is lost in mice expressing CETP.

Quantification of whole body adipose tissue volume by MRI

Whole mouse MRI was performed in a prone position on a 30 cm 7T horizontal MR scanner (Agilent, Palo Alto, CA) equipped with an Agilent quadrature transceiver cage coil with a 12 cm inner diameter gradient coil insert, a gradient strength of 600 mT/m, a rise time of 130 μs, and an inner diameter of 38 mm. carried out A pressure transducer for respiration monitoring and gating (used for shimming) was placed below the abdomen near the sternum. Monitor heart rate and oxygen saturation with a pulse oximeter on the right hind paw while maintaining anesthesia with 2.0-3.0% isoflurane in pure oxygen to target a respiratory rate between 80 and 120 BPM, and monitor body temperature with a rectal probe and warm air fan (SA Instruments, Stony Brook, NY) maintained at 37.0°C. Eight frequency shift scans reconstructed as sum of square roots, with isotropic voxels and FOV 70x36x36mm, matrix size 256x192x192, resolution 270x190x190μm, 30 degree flip angle, 8 TR/TE=4.8/2.4ms, 83kHz acquisition bandwidth, using 3D TFISP sequence, An asymmetric 500 μs pulse was used to image whole mice (excluding tail) for an acquisition time of 24 min. Mouse fat was quantified manually using ITK-SNAP (Yushkevich et al., Neuroimage. (2006) 31:1116-28).

To further study the interaction between Adcy9 and CETP, the effect of Adcy9 inactivation on body weight changes in CETP-expressing mice during arteriosclerosis treatment was investigated. CETP ^WT and CETP ^Gt mice showed similar body weight progression upon arteriosclerosis treatment ( FIG. 11A ). At sacrifice, body weights (CETP ^WT : 34.1±1.1 g; CETP ^Gt : 35.6±1.3 g) were similar to those of WT animals (33.5±1.2 g) and ^{Adcy9 Gt/Gt} mice (45.1±2.4 g, P<0.01, Figure 11a). ) was significantly lower than At week 14, adipose tissue volumes on MRI were similar in CETP ^WT (4.1±0.5 cm ³ ) and CETP ^Gt mice (5.4±0.7 cm ³ , FIG. 11B ). These results demonstrate that Adcy9 and CETP also interact in the regulation of body weight and obesity.

Example 11: Mouse model of myocardial infarction

A mouse model of myocardial infarction was generated by ligation of the left ventricular anterior descending (LAD) artery using sutures to mimic myocardial infarction caused by plague formation (Fig. 12b). By closing the LAD, no further blood flow is allowed in the area while the surrounding myocardial tissue is hardly affected. This surgical procedure mimics the pathobiological and pathophysiological aspects that occur in infarct-associated myocardial ischemia. These mice have four different genotypes: WT (wild-type mice); Adcy9 ^Gt/Gt (Adyc9 gene capture mice); tgCETP ^+/- (transgenic mice carrying a copy of the CETP gene); and Adcy9 ^Gt/Gt - tgCETP ^+/- (Adyc9 gene capture mice carrying a copy of the CETP gene) ( FIG. 12A ). All mice were of a C57BL/6J genetic background. 12C depicts a surgical timeline of a mouse infarct model by ligating the LAD. Echocardiography (“Echo”) was performed at baseline 24 hours, 1 week, and 4 weeks after surgery. Mice were 10±3 weeks old on D0 in the timeline.

Example 12: Genotyping Effects of Mice

The Kruskal-Wallis test was performed for the age ( FIG. 13A ) and body weight ( FIG. 13B ) of mice with four genotypes: WT (wild-type mice); Adcy9 ^Gt/Gt (Adyc9 gene capture mice); tgCETP ^+/- (transgenic mice carrying a copy of the CETP gene); and Adcy9 ^Gt/Gt - tgCETP ^+/- (Adyc9 gene capture mice carrying a copy of the CETP gene). No statistically significant differences were observed in age ( FIG. 13A ) and body weight ( FIG. 13B ) among mice with the four genotypes.

After 28 days, the survival of the mice was analyzed. No difference in survival was observed between mice with the four genotypes ( FIG. 13C ).

Example 13: Wall Motion Score Index (WMSI) Analysis

Echocardiography 24 hours post LAD-ligation for sham or myocardial infarction-induced ("MI") mice with four genotypes (WT, Adcy9 ^Gt/Gt , tgCETP ^+/- and Adcy9 ^Gt/Gt - tgCETP ^{+/- )} Wall Motion Score Index (WMSI) analysis was performed. Adcy9 ^Gt/Gt MI mice had lower WMSI compared to mice with other genotypes. See Figure 14a (all mice) and Figure 14b (live mice only). WMSI correlated with serum cardiac troponin-I (cTn-I) at 24 hours ( FIG. 15 ).

^{The reduced WMSI for Adcy9 Gt/Gt} mice observed 24 h after LAD-ligation is maintained over time as shown in FIG. 16A . As shown in Figure 19c, Adcy9 ^Gt/Gt MI mice had lower WMSI compared to mice with other genotypes. 16B shows a two-way repeated ANOVA analysis of myocardial infarction induced ("MI") mice with four genotypes (WT, Adcy9 ^Gt/Gt , tgCETP ^+/- and Adcy9 ^Gt/Gt - tgCETP ^{+/- ) (p} <0.001).

Example 14: Ischemic Myocardial Analysis

The Kruskal-Wallis test was performed on ischemic myocardial sections of mice with four genotypes. The portion of the ischemic myocardium was calculated according to FIG. 17A. Observations were made at +4 weeks after LAD-ligation. The proportion of ischemic myocardium is similar in the four genotypes ( FIG. 17B ).

Hearts of mice with four genetic backgrounds were sectioned for histological analysis as illustrated in FIG. 18A . Infarct size was estimated by attrition tricolor staining (FIG. 18b). The infarct size of mice was fit for different sections. The infarct size of Adcy9 ^Gt/Gt mice was significantly lower than that of wild-type and tgCETP ^{+/- mice.} Adcy9 ^{Gt / Gt} from mouse infarct size reduction Adcy9 ^{Gt / Gt} - it was less pronounced in tgCETP ^+/- mice (Fig. 19a and Fig. 19b).

The entire disclosure of each patent document and scientific publication mentioned herein is incorporated by reference for all purposes.

Claims (101)

a) CETP inhibitors; and
b) a method of treating or preventing congestive heart failure comprising administering to a subject in need thereof an effective amount of an ADCY inhibitor. The method of claim 1,
wherein administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. 3. The method according to claim 1 or 2,
CETP inhibitors are dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. 3. The method according to claim 1 or 2,
CETP inhibitors
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chlorothioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiopropionate;
S-[2-(1-Isopentylcyclohexanecarbonylamino)phenyl]phenoxy-thioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclopropanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]thioacetate;
S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclopentaincarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
O-methyl S-[2-(1-isopentylcyclohexanecarbonylaminophenyl monothiocarbonate;
S-[2-(1-methylcyclohexanecarbonylamino)phenyl]S-phenyldithiocarbonate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;
S-[2-(pivaloylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(2-cyclohexylpropionylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;
S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]disulfide;
2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonylamino)phenyl disulfide;
N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclohexanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiobenzoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;
bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]disulfide;
N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;
S-[2-1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate; or
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]-1-acetyl-piperidine-4-thiocarboxylate or a pharmaceutically acceptable salt of any of these. 5. The method according to any one of claims 1 to 4,
wherein the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. 6. The method according to any one of claims 1 to 5,
ADCY inhibitors include 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine;9-cyclopentyladenine;2',5'-dideoxyadenosine3'-diphosphate;2',5'-dideoxyadenosine3'-monophosphate;cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine);2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); 2-Amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)- quinazolinone, 2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP;3'-MANT-2'dATP;MANT-ATPγS;MANT-ITPγS;MANT-GTPγS;MANT-UTPγS;ANT-ATP;C1-ANT-ATP;C1-ANT-ITP;Br-ANT-ITP;Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; bis-MANT-ATP; bis-MANT-ITP; bis-MANT-CTP; bis-MANT-IDP; bis-MANT-IMP; bis-Cl-ANT-ATP; bis-Cl-ANT-ITP; bis-Br-ANT-ATP; bis-Br-ANT-ITP; bis-Pr-ANT-ATP; bis-Pr-ANT-ITP; bis-AcNH-ANT-ATP; bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP;araade;PMC6;NB001; Body P-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide;SB-268262;LRE1;2',5'-dideoxyadenosine;2',5'-dideoxyadenosine3'-triphosphate tetrasodium salt; adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylic acid cyclase-activating polypeptide; or a pharmaceutically acceptable salt of any of these. 7. The method according to any one of claims 1 to 6,
Subjects have genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs2531967/AA , rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. 7. The method according to any one of claims 1 to 6,
The method wherein the subject is known to have the genotype rs1967309/AA. 7. The method according to any one of claims 1 to 6,
Subjects have genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA , rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. 7. The method according to any one of claims 1 to 6,
Subjects had genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC , rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT. A method of treating or preventing congestive heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY compared to a control level, wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, wherein the CETP inhibitor is Dalcetrapib, Torcetrapib, Anacetrapib, Evacetrapib, Obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789 , BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. A method of treating or preventing congestive heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY compared to a control level, wherein reduced expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19- 4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of these. 13. The method according to claim 11 or 12,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. 14. The method of claim 13,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level. a) CETP inhibitors; and
b) a method of treating or preventing ventricular diastolic dysfunction comprising administering to a subject in need thereof an effective amount of an ADCY inhibitor. 16. The method of claim 15,
wherein administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. 17. The method according to claim 15 or 16,
CETP inhibitors are dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. 17. The method according to claim 15 or 16,
CETP inhibitors
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chlorothioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiopropionate;
S-[2-(1-Isopentylcyclohexanecarbonylamino)phenyl]phenoxy-thioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclopropanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]thioacetate;
S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclopentaincarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
O-methyl S-[2-(1-isopentylcyclohexanecarbonylaminophenyl monothiocarbonate;
S-[2-(1-methylcyclohexanecarbonylamino)phenyl]S-phenyldithiocarbonate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;
S-[2-(pivaloylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(2-cyclohexylpropionylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;
S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]disulfide;
2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonylamino)phenyl disulfide;
N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclohexanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiobenzoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;
bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]disulfide;
N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;
S-[2-1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate; or
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]-1-acetyl-piperidine-4-thiocarboxylate or a pharmaceutically acceptable salt of any of these. 19. The method according to any one of claims 15 to 18,
wherein the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. 20. The method according to any one of claims 15 to 19,
ADCY inhibitors include 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine;9-cyclopentyladenine;2',5'-dideoxyadenosine3'-diphosphate;2',5'-dideoxyadenosine3'-monophosphate;cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine);2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); 2-Amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)- quinazolinone; 2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP;3'-MANT-2'dATP;MANT-ATPγS;MANT-ITPγS;MANT-GTPγS;MANT-UTPγS;ANT-ATP;C1-ANT-ATP;C1-ANT-ITP;Br-ANT-ITP;Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; bis-MANT-ATP; bis-MANT-ITP; bis-MANT-CTP; bis-MANT-IDP; bis-MANT-IMP; bis-Cl-ANT-ATP; bis-Cl-ANT-ITP; bis-Br-ANT-ATP; bis-Br-ANT-ITP; bis-Pr-ANT-ATP; bis-Pr-ANT-ITP; bis-AcNH-ANT-ATP; bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP;araade;PMC6;NB001; Body P-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide;SB-268262;LRE1;2',5'-dideoxyadenosine;2',5'-dideoxyadenosine3'-triphosphate tetrasodium salt; adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylic acid cyclase-activating polypeptide; or a pharmaceutically acceptable salt of any of these. 21. The method according to any one of claims 15 to 20,
Subjects have genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs2531967/AA , rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. 21. The method according to any one of claims 15 to 20,
The method wherein the subject is known to have the genotype rs1967309/AA. 21. The method according to any one of claims 15 to 20,
Subjects have genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA , rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. 21. The method according to any one of claims 15 to 20,
Subjects had genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC , rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT. a) CETP inhibitors; and
b) a method of reducing the risk of ventricular diastolic insufficiency comprising administering to a subject in need thereof an effective amount of an ADCY inhibitor. 26. The method of claim 25,
wherein administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. 27. The method of claim 25 or 26,
CETP inhibitors are dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. 27. The method of claim 25 or 26,
CETP inhibitors
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chlorothioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiopropionate;
S-[2-(1-Isopentylcyclohexanecarbonylamino)phenyl]phenoxy-thioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclopropanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]thioacetate;
S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclopentaincarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
O-methyl S-[2-(1-isopentylcyclohexanecarbonylaminophenyl monothiocarbonate;
S-[2-(1-methylcyclohexanecarbonylamino)phenyl]S-phenyldithiocarbonate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;
S-[2-(pivaloylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(2-cyclohexylpropionylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;
S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]disulfide;
2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonylamino)phenyl disulfide;
N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclohexanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiobenzoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;
bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]disulfide;
N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;
S-[2-1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate; or
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]-1-acetyl-piperidine-4-thiocarboxylate or a pharmaceutically acceptable salt of any of these. 29. The method according to any one of claims 25 to 28,
wherein the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. 30. The method according to any one of claims 25 to 29,
ADCY inhibitors include 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine;9-cyclopentyladenine;2',5'-dideoxyadenosine3'-diphosphate;2',5'-dideoxyadenosine3'-monophosphate;cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine);2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); 2-Amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)- quinazolinone; 2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP;3'-MANT-2'dATP;MANT-ATPγS;MANT-ITPγS;MANT-GTPγS;MANT-UTPγS;ANT-ATP;C1-ANT-ATP;C1-ANT-ITP;Br-ANT-ITP;Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; bis-MANT-ATP; bis-MANT-ITP; bis-MANT-CTP; bis-MANT-IDP; bis-MANT-IMP; bis-Cl-ANT-ATP; bis-Cl-ANT-ITP; bis-Br-ANT-ATP; bis-Br-ANT-ITP; bis-Pr-ANT-ATP; bis-Pr-ANT-ITP; bis-AcNH-ANT-ATP; bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP;araade;PMC6;NB001; Body P-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide;SB-268262;LRE1;2',5'-dideoxyadenosine;2',5'-dideoxyadenosine3'-triphosphate tetrasodium salt; adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylic acid cyclase-activating polypeptide; or a pharmaceutically acceptable salt of any of these. 31. The method according to any one of claims 25 to 30,
Subjects have genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs2531967/AA , rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. 31. The method according to any one of claims 25 to 30,
The method wherein the subject is known to have the genotype rs1967309/AA. 31. The method according to any one of claims 25 to 30,
Subjects have genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA , rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. 31. The method according to any one of claims 25 to 30,
Subjects had genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC , rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT. A method of treating or preventing ventricular diastolic dysfunction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY compared to a control level, and , wherein a decreased expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, wherein the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19- 4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. A method of treating or preventing ventricular diastolic insufficiency comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY compared to a control level; , wherein a reduced expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19 -4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these. 37. The method of claim 35 or 36,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. 38. The method of claim 37,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level. A method of reducing the risk of ventricular diastolic insufficiency comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY compared to a control level; , wherein a reduced expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, wherein the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19- 4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. A method of reducing the risk of ventricular diastolic insufficiency comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY compared to a control level; , wherein a reduced expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19 -4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these. 41. The method of claim 39 or 40,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. 42. The method of claim 41,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level. a) CETP inhibitors; and
b) a method of treating or preventing ejection fraction-preserving heart failure comprising administering to a subject in need thereof an effective amount of an ADCY inhibitor. 44. The method of claim 43,
wherein administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. 45. The method of claim 43 or 44,
CETP inhibitors are dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. 45. The method of claim 43 or 44,
CETP inhibitors
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chlorothioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiopropionate;
S-[2-(1-Isopentylcyclohexanecarbonylamino)phenyl]phenoxy-thioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclopropanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]thioacetate;
S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclopentaincarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
O-methyl S-[2-(1-isopentylcyclohexanecarbonylaminophenyl monothiocarbonate;
S-[2-(1-methylcyclohexanecarbonylamino)phenyl]S-phenyldithiocarbonate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;
S-[2-(pivaloylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(2-cyclohexylpropionylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;
S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]disulfide;
2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonylamino)phenyl disulfide;
N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclohexanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiobenzoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;
bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]disulfide;
N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;
S-[2-1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate; or
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]-1-acetyl-piperidine-4-thiocarboxylate or a pharmaceutically acceptable salt of any of these. 47. The method according to any one of claims 43 to 46,
wherein the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. 48. The method according to any one of claims 43 to 47,
ADCY inhibitors include 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine;9-cyclopentyladenine;2',5'-dideoxyadenosine3'-diphosphate;2',5'-dideoxyadenosine3'-monophosphate;cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine);2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); 2-Amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)- quinazolinone; 2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP;3'-MANT-2'dATP;MANT-ATPγS;MANT-ITPγS;MANT-GTPγS;MANT-UTPγS;ANT-ATP;C1-ANT-ATP;C1-ANT-ITP;Br-ANT-ITP;Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; bis-MANT-ATP; bis-MANT-ITP; bis-MANT-CTP; bis-MANT-IDP; bis-MANT-IMP; bis-Cl-ANT-ATP; bis-Cl-ANT-ITP; bis-Br-ANT-ATP; bis-Br-ANT-ITP; bis-Pr-ANT-ATP; bis-Pr-ANT-ITP; bis-AcNH-ANT-ATP; bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP;araade;PMC6;NB001; Body P-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide;SB-268262;LRE1;2',5'-dideoxyadenosine;2',5'-dideoxyadenosine3'-triphosphate tetrasodium salt; adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylic acid cyclase-activating polypeptide; or a pharmaceutically acceptable salt of any of these. 49. The method according to any one of claims 43 to 48,
Subjects have genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs2531967/AA , rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. 49. The method according to any one of claims 43 to 48,
The method wherein the subject is known to have the genotype rs1967309/AA. 49. The method according to any one of claims 43 to 48,
Subjects have genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA , rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. 49. The method according to any one of claims 43 to 48,
Subjects had genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC , rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT. a) CETP inhibitors; and
b) a method of reducing the risk of heart failure with preservation of ejection fraction comprising administering to a subject in need thereof an effective amount of an ADCY inhibitor. 54. The method of claim 53,
wherein administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. 55. The method of claim 53 or 54,
CETP inhibitors are dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. 55. The method of claim 53 or 54,
CETP inhibitors
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chlorothioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiopropionate;
S-[2-(1-Isopentylcyclohexanecarbonylamino)phenyl]phenoxy-thioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclopropanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]thioacetate;
S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclopentaincarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
O-methyl S-[2-(1-isopentylcyclohexanecarbonylaminophenyl monothiocarbonate;
S-[2-(1-methylcyclohexanecarbonylamino)phenyl]S-phenyldithiocarbonate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;
S-[2-(pivaloylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(2-cyclohexylpropionylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;
S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]disulfide;
2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonylamino)phenyl disulfide;
N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclohexanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiobenzoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;
bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]disulfide;
N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;
S-[2-1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate; or
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]-1-acetyl-piperidine-4-thiocarboxylate or a pharmaceutically acceptable salt of any of these. 57. The method according to any one of claims 53 to 56,
wherein the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. 58. The method according to any one of claims 53 to 57,
ADCY inhibitors include 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine;9-cyclopentyladenine;2',5'-dideoxyadenosine3'-diphosphate;2',5'-dideoxyadenosine3'-monophosphate;cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine);2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); 2-Amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)- quinazolinone; 2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP;3'-MANT-2'dATP;MANT-ATPγS;MANT-ITPγS;MANT-GTPγS;MANT-UTPγS;ANT-ATP;C1-ANT-ATP;C1-ANT-ITP;Br-ANT-ITP;Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; bis-MANT-ATP; bis-MANT-ITP; bis-MANT-CTP; bis-MANT-IDP; bis-MANT-IMP; bis-Cl-ANT-ATP; bis-Cl-ANT-ITP; bis-Br-ANT-ATP; bis-Br-ANT-ITP; bis-Pr-ANT-ATP; bis-Pr-ANT-ITP; bis-AcNH-ANT-ATP; bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP;araade;PMC6;NB001; Body P-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide;SB-268262;LRE1;2',5'-dideoxyadenosine;2',5'-dideoxyadenosine3'-triphosphate tetrasodium salt; adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylic acid cyclase-activating polypeptide; or a pharmaceutically acceptable salt of any of these. 59. The method according to any one of claims 53 to 58,
Subjects have genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs2531967/AA , rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. 59. The method according to any one of claims 53 to 58,
The method wherein the subject is known to have the genotype rs1967309/AA. 59. The method according to any one of claims 53 to 58,
Subjects have genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA , rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. 59. The method according to any one of claims 53 to 58,
Subjects had genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC , rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT. A method of treating or preventing ejection fraction-preserving heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY compared to a control level; , wherein a reduced expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, wherein the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19- 4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. A method of treating or preventing ejection fraction-preserving heart failure comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY compared to a control level; , wherein a reduced expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19 -4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these. 65. The method of claim 63 or 64,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. 66. The method of claim 65,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level. A method of reducing the risk of heart failure with preserved ejection fraction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY as compared to a control level; , wherein a reduced expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, wherein the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19- 4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. A method of reducing the risk of heart failure with preserved ejection fraction comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY as compared to a control level; , wherein a reduced expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19 -4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these. 69. The method of claim 67 or 68,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. 70. The method of claim 69,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level. a) CETP inhibitors; and
b) a method of treating or preventing ventricular systolic insufficiency comprising administering to a subject in need thereof an effective amount of an ADCY inhibitor. 72. The method of claim 71,
wherein administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. 73. The method of claim 71 or 72,
CETP inhibitors are dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. 73. The method of claim 71 or 72,
CETP inhibitors
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chlorothioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiopropionate;
S-[2-(1-Isopentylcyclohexanecarbonylamino)phenyl]phenoxy-thioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclopropanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]thioacetate;
S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclopentaincarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
O-methyl S-[2-(1-isopentylcyclohexanecarbonylaminophenyl monothiocarbonate;
S-[2-(1-methylcyclohexanecarbonylamino)phenyl]S-phenyldithiocarbonate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;
S-[2-(pivaloylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(2-cyclohexylpropionylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;
S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]disulfide;
2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonylamino)phenyl disulfide;
N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclohexanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiobenzoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;
bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]disulfide;
N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;
S-[2-1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate; or
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]-1-acetyl-piperidine-4-thiocarboxylate or a pharmaceutically acceptable salt of any of these. 75. The method of any one of claims 71 to 74,
wherein the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. 76. The method of any one of claims 71 to 75,
ADCY inhibitors include 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine;9-cyclopentyladenine;2',5'-dideoxyadenosine3'-diphosphate;2',5'-dideoxyadenosine3'-monophosphate;cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine);2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); 2-Amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)- quinazolinone; 2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP;3'-MANT-2'dATP;MANT-ATPγS;MANT-ITPγS;MANT-GTPγS;MANT-UTPγS;ANT-ATP;C1-ANT-ATP;C1-ANT-ITP;Br-ANT-ITP;Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; bis-MANT-ATP; bis-MANT-ITP; bis-MANT-CTP; bis-MANT-IDP; bis-MANT-IMP; bis-Cl-ANT-ATP; bis-Cl-ANT-ITP; bis-Br-ANT-ATP; bis-Br-ANT-ITP; bis-Pr-ANT-ATP; bis-Pr-ANT-ITP; bis-AcNH-ANT-ATP; bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP;araade;PMC6;NB001; Body P-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide;SB-268262;LRE1;2',5'-dideoxyadenosine;2',5'-dideoxyadenosine3'-triphosphate tetrasodium salt; adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylic acid cyclase-activating polypeptide; or a pharmaceutically acceptable salt of any of these. 77. The method of any one of claims 71 to 76,
Subjects have genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs2531967/AA , rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. 77. The method of any one of claims 71 to 76,
The method wherein the subject is known to have the genotype rs1967309/AA. 77. The method of any one of claims 71 to 76,
Subjects have genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA , rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. 77. The method of any one of claims 71 to 76,
Subjects had genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC , rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT. a) CETP inhibitors; and
b) a method of reducing the risk of ventricular systolic insufficiency comprising administering to a subject in need thereof an effective amount of an ADCY inhibitor. 82. The method of claim 81,
wherein administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor. 83. The method of claim 81 or 82,
CETP inhibitors are dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. 83. The method of claim 81 or 82,
CETP inhibitors
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chlorothioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiopropionate;
S-[2-(1-Isopentylcyclohexanecarbonylamino)phenyl]phenoxy-thioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclopropanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]thioacetate;
S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclopentaincarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
O-methyl S-[2-(1-isopentylcyclohexanecarbonylaminophenyl monothiocarbonate;
S-[2-(1-methylcyclohexanecarbonylamino)phenyl]S-phenyldithiocarbonate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;
S-[2-(pivaloylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(2-cyclohexylpropionylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;
S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;
S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]disulfide;
2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonylamino)phenyl disulfide;
N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclohexanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thiobenzoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;
bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]disulfide;
N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;
S-[2-1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate; or
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]-1-acetyl-piperidine-4-thiocarboxylate or a pharmaceutically acceptable salt of any of these. 85. The method of any one of claims 81 to 84,
wherein the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor. 86. The method of any one of claims 81 to 85,
ADCY inhibitors include 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine;9-cyclopentyladenine;2',5'-dideoxyadenosine3'-diphosphate;2',5'-dideoxyadenosine3'-monophosphate;cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine);2-Amino-7-(4-chlorophenyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone;2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone;2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone); 2-Amino-7-(4-methoxyphenyl)-7,8-dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)- quinazolinone; 2-Amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; 2-Amino-7-(2-thienyl)-7,8-dihydro-5(6H)-quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT-UTP; 2'-MANT-3'dATP;3'-MANT-2'dATP;MANT-ATPγS;MANT-ITPγS;MANT-GTPγS;MANT-UTPγS;ANT-ATP;C1-ANT-ATP;C1-ANT-ITP;Br-ANT-ITP;Pr-ANT-ATP; Pr ANT-ITP; AcNH-ANT-ATP; AcNH-ANT-ITP; MANT-AppNHp; MANT-GppNHp; TNP-ATP; TNP-GTP; TNP-CTP; TNP-UTP; bis-MANT-ATP; bis-MANT-ITP; bis-MANT-CTP; bis-MANT-IDP; bis-MANT-IMP; bis-Cl-ANT-ATP; bis-Cl-ANT-ITP; bis-Br-ANT-ATP; bis-Br-ANT-ITP; bis-Pr-ANT-ATP; bis-Pr-ANT-ITP; bis-AcNH-ANT-ATP; bis-AcNH-ANT-ITP; NKY80; vidarabine; 2',5'-dd-3'-ATP;araade;PMC6;NB001; Body P-FS; 1,9-dd-FS; 6A7DA-FS; Calmidazolium; tyrphostin A25; 9-cyclopentyladenine monomethanesulfonate; (E)-2-(1H-benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene)propanehydrazide;SB-268262;LRE1;2',5'-dideoxyadenosine;2',5'-dideoxyadenosine3'-triphosphate tetrasodium salt; adrenocorticotropic hormone; brain natriuretic peptide (BNP); or a pituitary adenylic acid cyclase-activating polypeptide; or a pharmaceutically acceptable salt of any of these. 87. The method according to any one of claims 81 to 86,
Subjects have genotypes rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs2531967/AA , rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG. 87. The method according to any one of claims 81 to 86,
The method wherein the subject is known to have the genotype rs1967309/AA. 87. The method according to any one of claims 81 to 86,
Subjects have genotypes rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA , rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT. 87. The method according to any one of claims 81 to 86,
Subjects had genotypes rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC , rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT. A method of treating or preventing ventricular systolic insufficiency comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY compared to a control level; , wherein a reduced expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, wherein the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19- 4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. A method of treating or preventing ventricular systolic insufficiency comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY compared to a control level; , wherein a reduced expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19 -4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these. 93. The method of claim 91 or 92,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. 94. The method of claim 93,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level. A method of reducing the risk of ventricular systolic insufficiency comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY compared to a control level; , wherein a reduced expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10, wherein the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obisetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19- 4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of these. A method of reducing the risk of ventricular systolic insufficiency comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have a reduced expression or activity level of ADCY compared to a control level; , wherein a reduced expression or activity level of ADCY indicates that the subject will benefit from administration of a CETP inhibitor, wherein ADCY is ADCY9, wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19 -4789, or BAY 38-1315 or a pharmaceutically acceptable salt of any of these. 97. The method of claim 95 or 96,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's central nervous system compared to a control level. 98. The method of claim 97,
wherein the subject is known to have a reduced expression or activity level of ADCY in the subject's hypothalamus compared to a control level. 71. The method of any one of claims 1-70,
How the subject is human. 101. The method of claim 99,
wherein the subject is an adult human. 101. The method of claim 99,
The subject is a human child.

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