(57) Abstract: The present invention provides a novel galanin receptor protein GalR2 receptors. Also provided are nucleic acid sequences encoding the novel receptor proteins, and methods of use of this protein and the nucleic acid... more
(57) Abstract: The present invention provides a novel galanin receptor protein GalR2 receptors. Also provided are nucleic acid sequences encoding the novel receptor proteins, and methods of use of this protein and the nucleic acid sequence, as well as for galanin to develop and identify compounds for treating diseases and disorders involving it is a useful method. The importance of the disclosure is expressly to the action of galanin, they comprise antinociceptive activity, smooth muscle contraction, cardiovascular activity, pituitary hormone release, the recognition and increased food intake. Therefore, this receptor protein is useful for screening galanin agonist and antagonist activity to control these conditions.
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Iron overload is the major cause of morbidity and mortality in beta-thalassemia patients. The low levels of beta-globin and ineffective erythropoiesis in these patients result in the suppression of hepcidin. The inappropriately low levels... more
Iron overload is the major cause of morbidity and mortality in beta-thalassemia patients. The low levels of beta-globin and ineffective erythropoiesis in these patients result in the suppression of hepcidin. The inappropriately low levels of hepcidin trigger an increased absorption of dietary iron and increased iron release from storage, causing iron overload. Expression of hepcidin, which is predominately produced in the liver, is negatively regulated by the transmembrane protease, serine 6 (TMPRSS6). Mouse and human genetic data indicated that lowering TMPRSS6 expression could up-regulate hepcidin and ameliorate many of the disease symptoms associated with beta-thalassemia. Previously we identified a highly specific and potent antisense oligonucleotide (ASO) targeting either the murine (Guo et al. J Clin Invest. 2013; 123(4):1531-41) or the human (Aghajan et al, Blood 2016; 128:1013) TMPRSS6 mRNA. Downregulation of TMPRSS6 with ASO treatment resulted in dose-dependent hepcidin upr...
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The role of estradiol in mediating leptin’s effects on body weight was assessed in ovariectomized (OVX) mice before and after the onset of obesity. Ovariectomy did not alter leptin levels before the onset of obesity, and estradiol... more
The role of estradiol in mediating leptin’s effects on body weight was assessed in ovariectomized (OVX) mice before and after the onset of obesity. Ovariectomy did not alter leptin levels before the onset of obesity, and estradiol adminstration (0.05–17 μg/day for 14 days) did not significantly alter leptin levels if they were corrected for the estradiol-induced reduction in body fat. The converse was also true, in that leptin administration (0.4–140 μg/day) did not alter estradiol levels in intact mice. Furthermore, neither estradiol reduction (via ovariectomy) nor addition (via exogenous administration) significantly altered leptin’s ability to reduce fat mass. Leptin was equally effective in reducing body weight in lean or obese OVX mice and intact controls. Finally, estradiol did not change the magnitude of leptin’s effect on fat mass reduction when it was given in combination with leptin to lean intact or OVX mice. Estradiol may have indirectly affected leptin efficacy, because...
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Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause of worldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs... more
Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause of worldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs fibrolytic macrophage function remain ill defined. We studied the role of interleukin-4 receptor α (IL-4Rα), a potential central switch of macrophage polarization, in liver fibrosis progression and reversal. We demonstrate that inflammatory monocyte infiltration and liver fibrogenesis were suppressed in general IL-4Rαas well as in macrophage-specific IL-4Rα(IL-4Rα) mice. However, with deletion of IL-4Rαspontaneous fibrosis reversal was retarded. Results were replicated by pharmacological intervention using IL-4Rα-specific antisense oligonucleotides. Retarded resolution was linked to the loss of M2-type resident macrophages, which secreted MMP-12 through IL-4 and IL-13-mediated phospho-STAT6 activation. We conclude that IL-4Rα signaling regulates mac...
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Age-related macular degeneration (AMD) is the leading cause of permanent vision loss among the elderly in many industrialized countries, and the complement system plays an important role in the pathogenesis of AMD. Inhibition of... more
Age-related macular degeneration (AMD) is the leading cause of permanent vision loss among the elderly in many industrialized countries, and the complement system plays an important role in the pathogenesis of AMD. Inhibition of complement factor B, a key regulator of the alternative pathway, is implicated as a potential therapeutic intervention for AMD. Here we investigated the effect of liver factor B reduction on systemic and ocular factor B levels. Second-generation antisense oligonucleotides (ASOs) targeting mouse and monkey factor B mRNA were administered by subcutaneous injection to healthy mice or monkeys, and the level of factor B mRNA was assessed in the liver and the eye. In addition, the factor B protein level was determined in plasma and whole eyes from the treated animals. Mice and monkeys treated with factor B ASOs demonstrated a robust reduction in liver factor B mRNA levels with no change in ocular factor B mRNA levels. Plasma factor B protein levels were significan...
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Epithelial sodium channel (ENaC, Scnn1) hyperactivity in the lung leads to airway surface dehydration and mucus accumulation in cystic fibrosis (CF) patients and in mice with CF-like lung disease. We identified several potent ENaC... more
Epithelial sodium channel (ENaC, Scnn1) hyperactivity in the lung leads to airway surface dehydration and mucus accumulation in cystic fibrosis (CF) patients and in mice with CF-like lung disease. We identified several potent ENaC specific antisense oligonucleotides (ASOs) and tested them by inhalation in mouse models of CF-like lung disease. The inhaled ASOs distributed into lung airway epithelial cells and decreased ENaC expression by inducing RNase H1-dependent degradation of the targeted Scnn1a mRNA. Aerosol delivered ENaC ASO down-regulated mucus marker expression and ameliorated goblet cell metaplasia, inflammation, and airway hyper-responsiveness. Lack of systemic activity of ASOs delivered via the aerosol route ensures the safety of this approach. Our results demonstrate that antisense inhibition of ENaC in airway epithelial cells could be an effective and safe approach for the prevention and reversal of lung symptoms in CF and potentially other inflammatory diseases of the ...
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Current treatment of chronic hepatitis B virus infection (CHB) includes interferon and nucleos(t)ide analogues, which generally do not reduce HBV surface antigen (HBsAg) production, a constellation that is associated with poor prognosis... more
Current treatment of chronic hepatitis B virus infection (CHB) includes interferon and nucleos(t)ide analogues, which generally do not reduce HBV surface antigen (HBsAg) production, a constellation that is associated with poor prognosis of CHB. Here we evaluated the efficacy of an antisense approach using antisense oligonucleotide (ASO) technology already in clinical use for liver targeted therapy to specifically inhibit HBsAg production and viremia in a preclinical setting. A lead ASO was identified and characterized in vitro and subsequently tested for efficacy in vivo and in vitro using HBV transgenic and hydrodynamic transfection mouse and a cell culture HBV infection model, respectively. ASO treatment decreased serum HBsAg levels ⩾ 2 logs in a dose and time-dependent manner; HBsAg decreased 2 logs in a week and returned to baseline 4 weeks after a single ASO injection. ASO treatment effectively reduced HBsAg in combination with entecavir, while the nucleoside analogue alone did...
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ABSTRACT Extracts from bovine seminal vesicles have been shown to contain high concentrations of nerve growth factor (NGF)-like biological activity and of the NGF protein with properties corresponding to that of NGF from other sources. We... more
ABSTRACT Extracts from bovine seminal vesicles have been shown to contain high concentrations of nerve growth factor (NGF)-like biological activity and of the NGF protein with properties corresponding to that of NGF from other sources. We now demonstrate that a second neuronotrophic protein, termed seminal vesicle-derived neuronotrophic factor (SVNF), is present in seminal vesicle extracts (SVEs), which could not be distinguished from NGF on the basis of biological activity. SVNF has neuronotrophic activity on NGF target cells like embryonic chicken-sensory and sympathetic neurons, sympathetic neurons, and chromaffin cells from neonatal rats, but it is inactive on embryonic chicken ciliary or neonatal rat nodose ganglion neurons. It also stimulates fiber outgrowth from rat pheochromocytoma (PC 12) cells. In gel filtration chromatography on Biogel A 1.5 m, the activity is eluted with an apparent molecular weight of 40 kilodaltons, and by preparative isoelectric focusing, the isoelectric point was determined to be in the neutral range (6.8-7.8). The biological activity of SVNF, in contrast to that of NGF, is partially retained after preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis and can be electrophoretically eluted with an apparent molecular weight of 16-20 kilodaltons. Electrophoretically purified SVNF is not inhibited by antisera to mouse NGF, but its activity is increased greater than 10-fold in the presence of very low concentrations of NGF. For partially purified SVNF, a specific activity of 2.9-5.8 X 10(5) biological units/mg of protein was determined in the presence of subthreshold NGF concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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To preserve photoreceptor cell structure and function in a rodent model of retinitis pigmentosa with P23H rhodopsin by selective inhibition of the mutant rhodopsin allele using a second generation antisense oligonucleotide (ASO).... more
To preserve photoreceptor cell structure and function in a rodent model of retinitis pigmentosa with P23H rhodopsin by selective inhibition of the mutant rhodopsin allele using a second generation antisense oligonucleotide (ASO). Wild-type mice and rats were treated with ASO by intravitreal (IVT) injection and rhodopsin mRNA and protein expression were measured. Transgenic rats expressing the murine P23H rhodopsin gene (P23H transgenic rat Line 1) were administered either a mouse-specific P23H ASO or a control ASO. The contralateral eye was injected with PBS and used as a comparator control. Electroretinography (ERG) measurements and analyses of the retinal outer nuclear layer were conducted and correlated with rhodopsin mRNA levels. Rhodopsin mRNA and protein expression was reduced after a single ASO injection in wild-type mice with a rhodopsin-specific ASO. Transgenic rat eyes that express a murine P23H rhodopsin gene injected with a murine P23H ASO had a 181 ± 39% better maximum ...
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Leptin efficacy was compared in obese and lean female CD-1 mice. Body weights in these 10- to 12-mo-old mice ranged from 29.7 to 62.0 g, and leptin levels correlated with body weight. Mice from the lean and obese ends of the weight... more
Leptin efficacy was compared in obese and lean female CD-1 mice. Body weights in these 10- to 12-mo-old mice ranged from 29.7 to 62.0 g, and leptin levels correlated with body weight. Mice from the lean and obese ends of the weight distribution were treated with daily peripheral leptin injections (1-100 mg/kg) for a 33-day period. The half-maximal effective doses for weight loss and fat reduction were shifted 0.5-0.7 log to the right for obese mice. Leptin was less efficacious at low doses (1-3 mg/kg) in obese mice but equal to or more efficacious in obese than lean mice at high doses (30-100 mg/kg). Leptin's initial effects on weight loss could be explained by appetite suppression in both groups, but its effects on fat reduction were greater in leptin-treated than pair-fed mice, particularly in the lean group. Leptin also prevented the elevations in serum corticosterone and ketones found in pair-fed lean mice. These data allow a quantitative comparison of leptin sensitivity in ...
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We investigated the effect of inhibiting glycogenolysis on gluconeogenesis in 18-h-fasted conscious dogs with the use of intragastric administration of BAY R 3401, a glycogen phosphorylase inhibitor. Isotopic ([3-3H]glucose and... more
We investigated the effect of inhibiting glycogenolysis on gluconeogenesis in 18-h-fasted conscious dogs with the use of intragastric administration of BAY R 3401, a glycogen phosphorylase inhibitor. Isotopic ([3-3H]glucose and [U-14C]alanine) and arteriovenous difference methods were used to assess glucose metabolism. Each study consisted of a 100-min equilibration, a 40-min control, and two 90-min test periods. Endogenous insulin and glucagon secretions were inhibited with somatostatin (0.8 microgram.kg-1.min-1), and the two hormones were replaced intraportally (insulin: 0.25 mU.kg-1.min-1; glucagon: 0.6 ng.kg-1.min-1). Drug (10 mg/kg) or placebo was given after the control period. Insulin and glucagon were kept at basal levels in the first test period, after which glucagon infusion was increased to 2.4 ng.kg-1.min-1; BAY R 3401 decreased tracer-determined endogenous glucose production [rate of glucose production (Ra): 14 +/- 1 to 7 +/- 1 mumol.kg-1.min-1] and net hepatic glucose ...
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Alpha-1 antitrypsin (AAT) is a serum protease inhibitor that belongs to the serpin superfamily. Mutations in AAT are associated with α-1 antitrypsin deficiency (AATD), a rare genetic disease with two distinct manifestations: AATD lung... more
Alpha-1 antitrypsin (AAT) is a serum protease inhibitor that belongs to the serpin superfamily. Mutations in AAT are associated with α-1 antitrypsin deficiency (AATD), a rare genetic disease with two distinct manifestations: AATD lung disease and AATD liver disease. AATD lung disease is caused by loss-of-function of AAT and can be treated with plasma-derived AAT. AATD liver disease is due to the aggregation and retention of mutant AAT protein in the liver; the only treatment available for AATD liver disease is liver transplantation. Here we demonstrate that antisense oligonucleotides (ASOs) targeting human AAT efficiently reduce levels of both short and long human AAT transcript in vitro and in transgenic mice, providing a novel therapy for AATD liver disease. In addition, ASO-mediated depletion of mouse AAT may offer a useful animal model for the investigation of AATD lung disease.
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Recent clinical data strongly suggest that elevated urinary albumin excretion (UAE) identifies diabetic subjects at risk of developing nephropathy. Elevated UAE is attributed to increased transglomerular pressure, which is associated with... more
Recent clinical data strongly suggest that elevated urinary albumin excretion (UAE) identifies diabetic subjects at risk of developing nephropathy. Elevated UAE is attributed to increased transglomerular pressure, which is associated with poor metabolic control in rats. Because excess glucose in diabetes is metabolized via the polyol pathway, we were interested in whether the diabetes-induced elevation in UAE in rats could be prevented by inhibiting aldose reductase (AR), the first enzyme in the polyol pathway, with the AR inhibitor tolrestat. In fact, in rats made diabetic with streptozocin (35 mg/kg IV), treatment for 6 months with tolrestat (25 mg/kg/day in the diet) prevented both sorbitol accumulation in the kidney and the increase in UAE. Sorbitol accumulation and the increased UAE were not associated with statistically significant mesangial expansion, and the thickening of glomerular basement membranes was not affected by tolrestat treatment. The authors conclude that the 4.7-fold elevation in UAE in chronically diabetic rats is linked to the increased flux of glucose through the polyol pathway since it was prevented by inhibiting aldose reductase with tolrestat.
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1. Adv Exp Med Biol. 1987;223:97-104. The insulin-resistance inducing factor associated with uremia. Lockwood DH, Hayes GR, McCaleb ML. Department of Medicine, University of Rochester School of Medicine and Dentistry, NY 14642. ...
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Noradrenergic neurons in the hypothalamus involved in feeding and satiety are activated by gastrointestinal receptors. In the unrestrained rat, sites were first identified at which norepinephrine injected in the medial hypothalamus caused... more
Noradrenergic neurons in the hypothalamus involved in feeding and satiety are activated by gastrointestinal receptors. In the unrestrained rat, sites were first identified at which norepinephrine injected in the medial hypothalamus caused spontaneous feeding, or in the lateral hypothalamus caused no response. The activity of in vivo norepinephrine at these two sites was characterized by localized push-pull perfusion. When a nutrient was infused directly into the rat's duodenum, the synaptic release of hypothalamic norepinephrine was enhanced at lateral sites insensitive to norepinephrine, but suppressed at medial sites reactive to norepinephrine. Thus, signals from duodenal receptors are conceivably sent to the rat's brain to end feeding by way of noradrenergic inhibitory neurons in the hypothalamus.
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In male long Evans rats, microinjection cannulae were stereotaxically positioned to rest in sites in the preoptic area and medial hypothalamus. After the rats were satiated on wet mash, norepinephrine (NE) was infused in a dose of 2.5... more
In male long Evans rats, microinjection cannulae were stereotaxically positioned to rest in sites in the preoptic area and medial hypothalamus. After the rats were satiated on wet mash, norepinephrine (NE) was infused in a dose of 2.5 micrograms and a volume of 0.75 microliter into these diencephalic sites. At loci in six animals, NE evoked spontaneous feeding of 5.0 gms or more of wet mash. Cholecystokinin (CCK) infused prior to the NE microinjection either intraperitoneally (0.5--1.0 microgram/kg) or at the NE-sensitive hypothalamic sites (75--150 ng) significantly attenuated or blocked the rat's feeding response to NE. The intake of water was unaffected by CCK in both instances. Thus, CCK may act on the diencephalic noradrenergic feeding system indirectly, through vagal afferent pathways, or directly within the animal's hypothalamus.
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... injection of CCK issimilar to that seen either in the rat (ANTIN, GIBBS,HOLT, YOUNG & SMITH, 1975) or rabbit (HOUPT,ANIKA & WOLFF ... a 27 gauge stainless steelneedle of 22 mm in length was connected via a short lengthof PE-20... more
... injection of CCK issimilar to that seen either in the rat (ANTIN, GIBBS,HOLT, YOUNG & SMITH, 1975) or rabbit (HOUPT,ANIKA & WOLFF ... a 27 gauge stainless steelneedle of 22 mm in length was connected via a short lengthof PE-20 tubing to a 50 ^1 Hamilton syringe mounted ...
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Research Interests: Metabolism, Obesity, Glucose, Hyperglycemia, Animals, and 7 moreMale, Inositol, Fructose, Clinical Sciences, Rats, Sorbitol, and Glycosuria
It has been proposed by others that sulfonylureas exert their extrapancreatic hypoglycemic effects by increasing insulin binding through inhibition of receptor-mediated hormone internalization. In this study, we examined the possibility... more
It has been proposed by others that sulfonylureas exert their extrapancreatic hypoglycemic effects by increasing insulin binding through inhibition of receptor-mediated hormone internalization. In this study, we examined the possibility that the drugs act by inhibiting transglutaminase, an enzyme thought important in the internalization process. For ten days, male rats were fed pulverized chow containing either no drug, glipizide (5 mg/kg initial body wt/d), or tolazamide (75 mg/kg initial body wt/d). Prior to sacrifice, the six-hour fasting level of serum glucose was significantly reduced from 96 mg/100 ml in the control rats to 81 and 42 mg/100 ml in the glipizide- and tolazamide-treated rats, respectively. In contrast, the serum level of insulin was similar for all groups. The activity of transglutaminase in the postnuclear fraction of liver homogenate also was the same for all experimental groups. The specific binding of labeled insulin to purified liver plasma membranes was examined over a broad range of insulin concentrations; once again, there was no difference between experimental groups. Thus, the hypoglycemia caused by sulfonylurea administration could not be attributed to increases in insulin binding, inhibition of transglutaminase activity, or enhanced insulin levels. These data support our previous suggestion, based on in vitro studies, that sulfonylureas act predominately on processes beyond the binding portion of the insulin receptor.
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Compounds from two novel series of spirosuccinimides were prepared. Analogs of series 2 possessed a spiro-fused isoindolone moiety while those of series 3 contained a spiro-fused benzisothiazole S,S-dioxide group. These compounds were... more
Compounds from two novel series of spirosuccinimides were prepared. Analogs of series 2 possessed a spiro-fused isoindolone moiety while those of series 3 contained a spiro-fused benzisothiazole S,S-dioxide group. These compounds were evaluated as aldose reductase inhibitors (ARI) in vitro by their ability to inhibit glyceraldehyde reduction using a partially purified bovine lens aldose reductase preparation and in vivo as inhibitors of galactitol accumulation in the lens, sciatic nerve, and diaphragm of galactose-fed rats. Many members from the isoindolone series 2, particularly those containing an isoindolone N-methyl moiety, showed good in vitro and in vivo potency. The most potent member, the 6-chloro analog 32, was resolved, and aldose reductase activity was found to reside almost exclusively in the (+)-enantiomer. Compound 32 was approximately equipotent in the sciatic nerve of the galactose-fed rat to other cyclic imide ARI's of similar in vitro activity, namely sorbinil and ADN-138 and also to tolrestat, an acetic acid-based ARI (ED50's 4-8 mg/kg). Compounds from both series, 2 and 3, were also found to lower plasma glucose levels of genetically obese db/db and ob/ob mice with potency similar to that of ciglitazone. However, members from these series failed to lower insulin levels of the ob/ob mouse at the doses tested.
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Bioisosteric substitution was used as a tool to generate several new structural alternatives to the thiazolidine-2,4-dione and tetrazole heterocycles as potential antidiabetic agents. Among the initial leads that emerged from this... more
Bioisosteric substitution was used as a tool to generate several new structural alternatives to the thiazolidine-2,4-dione and tetrazole heterocycles as potential antidiabetic agents. Among the initial leads that emerged from this strategy, a family of acidic azoles, isoxazol-3- and -5-ones and a pyrazol-3-one, showed significant plasma glucose-lowering activity (17-42% reduction) in genetically obese, diabetic db/db mice at a dose of 100 mg/kg/day x4. Structure-activity relationship studies determined that 5-alkyl-4-(arylmethyl)pyrazol-3-ones, which exist in solution as aromatic enol/iminol tautomers, were the most promising new class of potential antidiabetic agent (32-45% reduction at 20 mg/kg/d x4). Included in this work are convenient syntheses for several types of acidic azoles that may find use as new acidic bioisosteres in medicinal chemistry such as the antidiabetic lead 5-(trifluoromethyl)pyrazol-3-one (hydroxy tautomer) and aza homologs of the pyrazolones, 1,2,3-triazol-5-ones (hydroxy tautomer) and 1,2,3,4-tetrazol-5-one heterocycles. log P and pKa data for 15 potential acidic bioisosteres, all appended to a 2-naphthalenylmethyl residue so as to maintain a similar distance between the acidic hydrogen and arene nucleus, are presented. This new data set allows comparison of a wide variety of potential acid mimetics (pKa 3.78-10.66; log P -0.21 to 2.76) for future drug design.
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Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones and 5-(3-aryl-2-propynyl)-5-(arylsulfanyl)thiazolidine-2,4-diones were prepared and evaluated as oral antihyperglycemic agents in the obese, insulin resistant db/db mouse... more
Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones and 5-(3-aryl-2-propynyl)-5-(arylsulfanyl)thiazolidine-2,4-diones were prepared and evaluated as oral antihyperglycemic agents in the obese, insulin resistant db/db mouse model at 100 mg/kg and, if the analogue had sufficient potency, 20 mg/kg. The sulfonylthiazolidinediones, 2, were more potent than the corresponding sulfanylthiazolidinedione congeners, 1. With regard to substituent effects on the 3-propynyl phenyl ring (Ar') of 2, 4-halogen substitution generally resulted in the more potent analogues. Substituent effects on the phenylsulfonyl moiety (Ar) of 2 were less clear, although para-halogen substitution on Ar generally was preferable. 2-Pyridinesulfonyl derivatives (Ar = 2-pyridine in 2) also had good potency. Several compounds from series 2 were effective at lowering glucose and insulin in the obese, insulin resistant ob/ob mouse at the 50 mg/kg oral dose. Compound 20 significantly improved the glucose tolerance of obese, insulin resistant Zucker rats at the 20 mg/kg dose level and had no effect on plasma glucose or on glucose tolerance in normal rats fasted for 18 h at the 100 mg/kg level.
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The synthesis, structure-activity relationship (SAR) studies, and antidiabetic characterization of 1,2-dihydro-4-[[4-(methylthio)phenyl]methyl]-5-(trifluoromethyl)-3H- pyrazol-3-one (as the hydroxy tautomer; WAY-123783, 4) are described.... more
The synthesis, structure-activity relationship (SAR) studies, and antidiabetic characterization of 1,2-dihydro-4-[[4-(methylthio)phenyl]methyl]-5-(trifluoromethyl)-3H- pyrazol-3-one (as the hydroxy tautomer; WAY-123783, 4) are described. Substitution of 4-methylthio, methylsulfinyl, or ethyl to a benzyl group at C4, in combination with trifluoromethyl at C5 of pyrazol-3-one, generated potent antihyperglycemic agents in obese, diabetic db/db mice (16-30% reduction in plasma glucose at 2 mg/kg). The antihyperglycemic effect was associated with a robust glucosuria (> 8 g/dL) observed in nondiabetic mice. Chemical trapping of four of the seven possible tautomeric forms of the heterocycle by mono- and dialkylation at the acidic hydrogens provided several additional potent analogs (39-43% reduction at 5 mg/kg) of the lead 4 as well as a dialkylated pair of regioisomers that showed separation of the associated glucosuric effect produced by all of the active analogs in normal mice. Further pharmacological characterization of the lead WAY-123783 (ED50 = 9.85 mg/kg, po in db/db mice), in oral and subcutaneous glucose tolerance tests, indicated that unlike the renal and intestinal glucose absorption inhibitor phlorizin, pyrazolone 4 does not effectively block intestinal glucose absorption. SAR and additional pharmacological data reported herein suggest that WAY-123783 represents a new class of potent antihyperglycemic agents which correct hyperglycemia by selective inhibition of renal tubular glucose reabsorption.
Research Interests: Organic Chemistry, Medicinal Chemistry, Blood Glucose, Mice, Animals, and 11 moreAbsorption, Rats, Medicinal, Oral Hypoglycemic Agents, Pyrazoles, Glucose Tolerance Test, Type 2 Diabetes Mellitus, Structure activity Relationship, Glycosuria, Molecular Structure, and Pharmacology and pharmaceutical sciences
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Research Interests: Biological Chemistry, Mammals, Biological Sciences, Humans, Mice, and 15 moreFemale, Animals, Male, Biological, Polymerase Chain Reaction, CHEMICAL SCIENCES, Introns, Molecular cloning, Molecular Characterization, Gestational Age, Amino Acid Sequence, Base Sequence, Molecular Sequence Data, frameshift mutation, and Medical and Health Sciences
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We report isolation of a murine gene, NPYR-D, which predicts an intronless novel G protein-coupled receptor of 375 amino acids. Percent identities of NPYR-D to the clone Y1, Y2, rat Y4/PP1 and human Y4/PP1 receptors are 45, 32, 92 and 76,... more
We report isolation of a murine gene, NPYR-D, which predicts an intronless novel G protein-coupled receptor of 375 amino acids. Percent identities of NPYR-D to the clone Y1, Y2, rat Y4/PP1 and human Y4/PP1 receptors are 45, 32, 92 and 76, respectively. Southern blots indicate that NPYR-D and human Y4/PP1 receptor genes are species homologues. Rat [125I]pancreatic polypeptide ([125I]rPP) bound to NPYR-D transfected COS-7 cell membranes with a high affinity, i.e. IC50=90 pM. Pharmacological characterization of [125I]rPP binding showed a rank order of potency of P > PYY > or = NPY, such that PYY and NPY were at least 5000-fold weaker than PP. Interestingly, [125I]rPYY binding produced the same rank order, but PYY and NPY were only 25-fold weaker than PP, which had an IC50 value of approximately 120 pM. Tissue distribution studies in mouse and humans suggest potential roles of this novel receptor in the gastrointestinal tract, heart, prostate, as well as in neural and endocrine signalling.
Research Interests: Kinetics, Gene expression, Cercopithecus aethiops, Cell line, Humans, and 15 moreMice, Animals, Male, Polymerase Chain Reaction, Gene Structure, Molecular cloning, Rats, Neuropeptide Y, Gastrointestinal Tract, Amino Acid Profile, Amino Acid Sequence, Base Sequence, Biochemistry and cell biology, Molecular Sequence Data, and Cell Membrane
A series of 1,2,4-oxadiazolidine-3,5-diones was synthesized and evaluated as oral antihyperglycemic agents in the obese insulin resistant db/db and ob/ob mouse - the two models for Type 2 diabetes mellitus. The majority of the prepared... more
A series of 1,2,4-oxadiazolidine-3,5-diones was synthesized and evaluated as oral antihyperglycemic agents in the obese insulin resistant db/db and ob/ob mouse - the two models for Type 2 diabetes mellitus. The majority of the prepared methoxy- and ethoxy-linked oxazole 1,2,4-oxadiazolidine-3,5-diones normalized plasma glucose levels at the 100 mg kg(-1) oral dose in the db/db diabetic mouse model, and several amongst them reduced the glucose levels at the 20 mg kg(-1) oral dose. The most potent compounds in the db/db mouse model were also active in the ob/ob mouse model normalizing the plasma glucose levels at the 20 mg kg(-1) oral dose. The trifluoromethoxy analog 32 was the most active compound of the series, reducing significantly the plasma glucose levels at the 5 mg kg(-1) oral dose. Oxadiazole-tailed 1,2,4-oxadiazolidine-3,5-diones were also active in both the db/db and ob/ob diabetic mouse models normalizing plasma glucose levels at the 100 mg kg(-1) oral dose.
Research Interests: Organic Chemistry, Type 2 Diabetes, Blood Glucose, Insulin, Mice, and 12 moreFemale, Animals, Male, Peroxisome proliferator-activated receptor, European, Mouse Model, Oral Hypoglycemic Agents, Thiazoles, Type 2 Diabetes Mellitus, Structure activity Relationship, Plasma Glucose, and Pharmacology and pharmaceutical sciences
Research Interests: Blood Glucose, Capillaries, Basement Membrane, Diabetic Retinopathy, Female, and 15 moreAnimals, Retina, Diabetic Nephropathy, Blood Urea Nitrogen, Clinical Sciences, Rats, Public health systems and services research, Albuminuria, Streptozotocin, Diabetic Rat, Glycosuria, Creatinine, aldose reductase, Diabetic Neuropathies, and Paediatrics and reproductive medicine
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... 0361-9230/79/050651-06$01.10/0 652 MC CALEB AND MYERS 22 C. The animals ranged in weight between 310 to 490 g and were maintained on a 12-hr light-dark cycle. ... 1, BOTTOM). The overall activity of "H-NE also was not modified by... more
... 0361-9230/79/050651-06$01.10/0 652 MC CALEB AND MYERS 22 C. The animals ranged in weight between 310 to 490 g and were maintained on a 12-hr light-dark cycle. ... 1, BOTTOM). The overall activity of "H-NE also was not modified by MC CALEB AND MYERS FIG. ...