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WO2008064264A2 - Procédés in vivo d'identification et de criblage de composés qui modulent la liaison de calstabine à un récepteur de ryanodine - Google Patents

Procédés in vivo d'identification et de criblage de composés qui modulent la liaison de calstabine à un récepteur de ryanodine Download PDF

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Publication number
WO2008064264A2
WO2008064264A2 PCT/US2007/085298 US2007085298W WO2008064264A2 WO 2008064264 A2 WO2008064264 A2 WO 2008064264A2 US 2007085298 W US2007085298 W US 2007085298W WO 2008064264 A2 WO2008064264 A2 WO 2008064264A2
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WO
WIPO (PCT)
Prior art keywords
calstabin
binding
compound
tissue
receptor
Prior art date
Application number
PCT/US2007/085298
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English (en)
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WO2008064264A8 (fr
Inventor
Jian Shan
Andrew Marks
Rita Kirk
Steven Reiken
Stephan Elmar Lehnart
Original Assignee
Armgo Pharma, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Armgo Pharma, Inc. filed Critical Armgo Pharma, Inc.
Publication of WO2008064264A2 publication Critical patent/WO2008064264A2/fr
Publication of WO2008064264A8 publication Critical patent/WO2008064264A8/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/91188—Transferases (2.) transferring nitrogenous groups (2.6)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/02—Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)

Definitions

  • Calstabin binding to RyR can be regulated by covalent modifications to RyR.
  • calstabin-2 binding to RyR2 is regulated by protein kinase A (PKA)-mediated mediated phosphorylation of Ser2809 in RyR2.
  • PKA phosphorylation of RyR2 decreases the binding affinity of calstabin-2, causing calstabin-2 dissociation and increasing RyR2 open probability (Po) and its sensitivity to Ca 2+ -dependent activation.
  • PKA- phosphorylated RyR is an important part of the "fight or flight" response, by which the sympathetic nervous system (SNS), in response to stress or exercise, enhances myocardial contractility and increases cardiac output.
  • SNS sympathetic nervous system
  • the activated sympathetic nervous system produces catecholamines (noradrenalin and adrenalin), which stimulate a beta adrenergic signaling cascade that results in a transient increase in PKA-phosphorylation of
  • HF myocardial contractility
  • the most common cardiac arrhythmia in humans is atrial fibrillation (AF), which can lead to aberrant structural and electrical remodeling of the heart.
  • AF atrial fibrillation
  • Fatal cardiac arrhythmias account for nearly half of all HF deaths, the majority resulting from ventricular arrhythmias.
  • Ventricular arrhythmias can be rapidly fatal and include sudden cardiac death (SCD).
  • SCD sudden cardiac death
  • CPVT catecholaminergic polymorphic ventricular tachycardia
  • RyR2 missense mutations all of which decrease the binding affinity of calstabin-2 for RyR2.
  • SCD SCD in up to 50% of afflicted individuals by 35 years of age.
  • CPVT individuals have structurally normal hearts and do not develop ventricular arrhythmias when at rest, but are prone to ventricular arrhythmias in response to stress or exercise.
  • Studies of heterologously expressed CPVT-mutant RyR2 channels reveal a significant intracellular leak during beta-adrenergic stimulation.
  • intracellular calcium signaling is critical to neuronal signaling, with the main source of intracellular calcium being released from internal stores and RyRs, but not inositol 1,4,5- triphosphate (IP3) receptors, which are another endoplasmic calcium release channel, appearing to modulate cellular protein synthesis.
  • IP3 inositol 1,4,5- triphosphate
  • Isoproterenol is a synthetic beta-adrenergic receptor agonist that causes PKA activation and RyR phosphorylation, mimicking the hyperadrenergic state that occurs during heart failure and muscle fatigue.
  • chronic application of isoproterenol by osmotic mini-pump for a period of at least 5 days mimics chronic sympathetic nervous system activation as occurs in disease processes on the heart, skeletal muscle, or other organs of interest.
  • the invention thus provides a powerful in vivo animal model of disease conditions that are associated with abnormal or dysfunctional ryanodine receptor such as heart failure and muscle fatigue.
  • the invention provides an in vivo method for identifying a compound that produces a change or increase in calstabin binding to a ryanodine receptor, which method comprises administering to an animal a physiologically effective amount of a regulating compound, e.g., a beta adrenergic agonist such as isoproterenol or an agonist of the cyclic- AMP signaling pathways such as a PKA agonist, that induces phosphorylation of ryanodine receptors leading to decreased calstabin binding to such receptors and then measuring calstabin binding to such receptors in that animal; administering to another, similar animal the same amount of the regulating compound in combination with an amount of a test compound and measuring calstabin binding to a ryanodine receptor in that animal; and comparing the measured calstabin binding for each animal to determine whether the test compound changes or increases calstabin binding to a ryanodine receptor.
  • a regulating compound e.g., a beta
  • FIGs. 3 A and B show the levels of RyR, phospho-RyR (Ser-2809), and calstabin-2 in immunoprecipitated RyR complexes from heart lysates and calstabin-1 in immunoprecipitated RyR complexes from tibialis lysates in mice (male and female) administered vehicle, isoproterenol alone (no drug) or isoproterenol together with l ⁇ l per hour of 0.36 mM, 1.8 mM, 3.6 mM, 7.2 mM, or 36 mM ARM 036 for 5 days (corresponding to 0.09, 0.44, 0.88, 1.76 and 8.81 mg/kg/day, respectively of ARM036 based on the average weight of the animals), by western blot (A) and densitometric analysis (B); FIG. 3C shows the plasma exposure levels of ARM036 five days after osmotic pump administration;
  • FIGs. 7A and B show levels of calstabin-2 in immunoprecipitated RyR2 complexes from heart lysates in male and female rats receiving osmotic pump administration of isoproterenol for 5 days with or without 0.22, 1.11, 2.22, 4.44 and 22.18 mg/kg/day ARM036 (based on the average weight of the animals), by immunoblot assay (A) and densitometric analysis (B); and
  • the invention provides in vivo methods for measuring a change in calstabin binding to a ryanodine receptor, which comprises chronically administering to an animal a physiologically effective amount of a compound that regulates the binding of a calstabin to a ryanodine receptor and measuring the binding of the calstabin to the ryanodine receptor in a tissue from the animal.
  • This in vivo method for measuring a change in calstabin binding to a ryanodine receptor provides a basis for identifying and screening compounds that modulate calstabin binding to a ryanodine receptor in vivo.
  • Ri is selected from the group consisting of H, oxo, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl; wherein each alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl may be substituted or unsubstituted;
  • Rn, Ri 2 , Ri 3 , and R 14 independently are selected from the group consisting of H, OH, NH 2 , - NHNH 2 , -NHOH, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
  • the term "treating" or "treatment” of a disorder or disease includes (1) preventing or delaying the appearance of clinical symptoms of the disorder or disease developing in a mammal that may be afflicted with or predisposed to the disorder or disease but does not yet experience or display clinical or subclinical symptoms of the disorder or disease; or (2) inhibiting the disorder or disease, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease or disorder, i.e., causing regression of the disease or disorder or at least one of its clinical or sub-clinical symptoms.
  • skeletal muscular disorder and diseases include, but are not limited to, muscle fatigue that results from pathologies, illnesses, diseases, disorders or conditions that are associated with the RyR receptors that regulate calcium channel functioning in cells.
  • disorders and conditions include, but are not limited to, cardiac disease or disorder, defective skeletal muscle function, HIV Infection, AIDS, muscular dystrophy, cancer, malnutrition, exercise-induced muscle fatigue, age-associated muscle fatigue, renal disease, renal failure, bladder disorders, incontinence, malignant hypothermia, and central core disease.
  • the term "increasing binding” or “enhancing binding” or “enhancing reassociation” includes enhancing, increasing, or improving the ability of RyR (e.g., phosphorylated RyR) to associate physically with FKBP (e.g., binding of approximately two fold or, approximately five fold, above the background binding of a negative control) in a tissue sample or cells of the subject and enhancing, increasing or improving the ability of FKBP to associate physically with RyR (e.g., binding of approximately two fold, or, approximately five fold, above the background binding of a negative control) in cells of the subject.
  • RyR e.g., phosphorylated RyR
  • FKBP e.g., binding of approximately two fold or, approximately five fold, above the background binding of a negative control
  • the invention provides in vivo methods for identifying compounds that modulate binding of a calstabin to a ryanodine receptor and that can be used to treat diseases associated with RyRs.
  • the methods involve administering to an animal, e.g., a mouse or another mammal such as a rat, a dog, or a pig, a physiologically effective amount of a regulating compound that regulates or decreases calstabin binding to a ryanodine receptor and then measuring calstabin binding to such receptor in that animal; administering to another, similar animal the same amount of the regulating compound in combination with an amount of a test compound and measuring calstabin binding to a ryanodine receptor in that animal; and comparing the measured calstabin binding in a tissue from each animal to determine whether the test compound changes or increases calstabin binding to the ryanodine receptor.
  • an animal e.g., a mouse or another mammal such as a rat, a dog, or
  • the regulating compound is a beta agonist, preferably isoproterenol, and has an effective amount of approximately 0.5 mg/kg/hr, when administered by an osmotic pump that has been implanted subcutaneous Iy in a mouse.
  • the beta agonist is chronically administered to the subject, for example, for three to five days.
  • in vivo binding of calstabin to RyR can be measured by extracting tissue samples, making lysates, immunoprecipitating RyR complexes from the lysates, and analyzing the complexes for the presence of calstabin. Levels of phosphorylated-RyR and total RyR can also be determined.
  • protein is isolated and purified from cells of a subject using standard methods known in the art, including, without limitation, extraction from the cells (e.g., with a detergent that solubilizes the protein) where necessary, followed by affinity purification on a column chromatography (e.g., FTLC and HPLC), immunoprecipitation (with an antibody), and precipitation (e.g., with isopropanol and a reagent such as TRIzol). Isolation and purification of the protein is followed by electrophoresis (e.g., on an SDS-polyacrylamide gel) The level of PKA phosphorylation of RyR, which correlates with the degree of heart failure, can also be assayed to measure the RyR-calstabin interaction.
  • a preferred assay for measuring the efficacy of the regulatory compound involves immunoblotting methods with a phosphoepitope-specific antibody, which detects RyRl that is PKA phosphorylated on Ser 2843, or which detects RyR2 that is PKA phosphorylated on Ser 2809. Immunoblotting with such antibody can be used to measure the effect of the regulating compound on the levels of phosphorylated RyR. Simultaneous examination of the levels of phospho-RyR and calstabin provides confirmation of the effects of the regulating compounds. For example, in mice treated with a regulating compound that stimulates PKA-mediated phosphorylation of the RyR, total levels of RyR should not be significantly affected. On the other hand, the levels of phospho-RyR should be increased, while the levels of associated calstabin should be decreased.
  • separate groups of animals can be treated with beta-adrenergic agonist for various time periods (e.g., at least about 3 days, about 4 days or about 5 days), as well as with a control solution lacking the agonist.
  • time periods e.g., at least about 3 days, about 4 days or about 5 days
  • a control solution lacking the agonist. Comparing the levels of calstabin in immunoprecipitated RyR complexes in heart tissue extracts isolated from the groups provides a measurement of calstabin dissociation in the presence of the drug over time, as well as a measurement of the actual reduction in bound calstabin compared against the control group.
  • hetero-aryl (hetero-)arylthio, and (hetero-)arylamino may be substituted or unsubstituted;
  • Ri is selected from the group consisting of H, oxo, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl; wherein each alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl may be substituted or unsubstituted;
  • R 6 is selected from the group consisting of -ORi 5 , -NHNRi 5 Ri 6 , -NHOH, -NRi 5 Ri 6 , -CH 2 X, acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
  • Ri5 and Ri 6 independently are selected from the group consisting of H, acyl, alkenyl, alkoxyl, OH, NH 2 , alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted; and optionally R15 and Ri 6 together with the N to which they are bonded may form a heterocycle which may be substituted; and the nitrogen in the benzothiazepine ring may optionally be a quaternary nitrogen, and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts,
  • test compound is preferably administered as is, without further processing. If desired, however, the compound can be administered in a pharmaceutical formulation, e.g., in admixture with a suitable pharmaceutical excipient, diluent, or carrier selected with regard to the intended route of administration and standard pharmaceutical practices. Accordingly, in one aspect, the invention provides a pharmaceutical composition or formulation comprising at least one test compound, or a pharmaceutically acceptable derivative thereof, as the active ingredient in association with a pharmaceutically acceptable excipient, diluent and/or carrier that is compatible with the other ingredients of the formulation and that is not deleterious to the recipient thereof.
  • the regulating agent can be administered for a time sufficient to elicit a biological effect such as RyR phosphorylation and concomitant decrease in calstabin binding to RyR, followed by a single bolus administration of the test compound (e.g., by oral gavage, injection, or the like).
  • mice were given the following regimen: osmotic pump administration of vehicle; osmotic pump administration of isoproterenol for 5 days; osmotic pump administration of isoproterenol for 5 days together with 0.54, 1.09 or 2.17 mg/kg/day ARM036 free acid (based on the average weight of the animals); and osmotic pump administration of isoproterenol for 5 days together with once-daily oral administration by gavage of either 4.19, 8.36 or 16.72 mg/kg/day ARM036 sodium salt (based on the average weight of the animals, doses expressed as the free acid.). Animals were sacrificed 2 hours post the final oral dose, tissue was harvested, and RyR was immunoprecipitated and calstabin rebinding was quantified as described above.

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Abstract

L'invention concerne des procédés in vivo d'identification et de criblage de composés qui modulent la liaison de calstabine à un récepteur de la ryanodine. Les procédés comprennent la comparaison de la liaison de calstabine mesurée à un tel récepteur dans un tissu provenant d'un premier animal auquel a été administrée une quantité physiologiquement efficace d'un composé régulant la liaison de calstabine à la liaison de calstabine mesurée à un tel récepteur dans un tissu provenant d'un autre animal similaire auquel a été administrée une quantité du composé régulateur en combinaison avec une quantité d'un composé d'essai pour déterminer si le composé d'essai modifie la liaison de calstabine sur un tel récepteur de ryanodine. La liaison de calstabine sur un récepteur de ryanodine chez un sujet peut être modifiée ou augmentée par administration d'un composé identifié à partir des présents procédés in vivo. L'invention concerne également un modèle animal in vivo imitant les conditions associées à un récepteur de ryanodine anormale ou dysfonctionnelle telles qu'une insuffisance cardiaque et une fatigue musculaire.
PCT/US2007/085298 2006-11-20 2007-11-20 Procédés in vivo d'identification et de criblage de composés qui modulent la liaison de calstabine à un récepteur de ryanodine WO2008064264A2 (fr)

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US86655606P 2006-11-20 2006-11-20
US60/866,556 2006-11-20

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WO2008064264A2 true WO2008064264A2 (fr) 2008-05-29
WO2008064264A8 WO2008064264A8 (fr) 2008-12-24

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010114562A1 (fr) * 2009-04-03 2010-10-07 Sequel Pharmaceuticals, Inc. Procedes d'administration ameliores de k201 (jtv-519) (4-[3-{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy 2, 3, 4, 5-tetrahydro-1, 4-benzothiazepine monochlorhydrate)
EP2653466A1 (fr) 2012-04-18 2013-10-23 Les Laboratoires Servier Agents pour le traitement de troubles impliquant la modulation de récepteurs de la ryanodine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
No Search *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010114562A1 (fr) * 2009-04-03 2010-10-07 Sequel Pharmaceuticals, Inc. Procedes d'administration ameliores de k201 (jtv-519) (4-[3-{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy 2, 3, 4, 5-tetrahydro-1, 4-benzothiazepine monochlorhydrate)
EP2653466A1 (fr) 2012-04-18 2013-10-23 Les Laboratoires Servier Agents pour le traitement de troubles impliquant la modulation de récepteurs de la ryanodine
WO2013156505A1 (fr) 2012-04-18 2013-10-24 Les Laboratoires Servier Agents pour le traitement de troubles mettant en jeu la modulation de récepteurs de ryanodine
US8853198B2 (en) 2012-04-18 2014-10-07 Les Laboratoires Servier Agents for treating disorders involving modulation of ryanodine receptors
MD4489C1 (ro) * 2012-04-18 2018-01-31 Les Laboratoires Servier Derivaţi de 1,4-benzotiazepină, procedeu de sinteză a lor, compoziţii farmaceutice care le conţin şi utilizarea acestora pentru tratarea sau prevenirea afecţiunilor care implică modularea receptorilor de rianodină
EP2708535A1 (fr) 2012-05-11 2014-03-19 Les Laboratoires Servier Agents pour le traitement de troubles impliquant la modulation de récepteurs de la ryanodine

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