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1.
J Pharmacol Exp Ther ; 377(2): 293-304, 2021 05.
Article in English | MEDLINE | ID: mdl-33602875

ABSTRACT

In failing hearts, Na+/Ca2+ exchanger (NCX) overactivity contributes to Ca2+ depletion, leading to contractile dysfunction. Inhibition of NCX is expected to normalize Ca2+ mishandling, to limit afterdepolarization-related arrhythmias, and to improve cardiac function in heart failure (HF). SAR340835/SAR296968 is a selective NCX inhibitor for all NCX isoforms across species, including human, with no effect on the native voltage-dependent calcium and sodium currents in vitro. Additionally, it showed in vitro and in vivo antiarrhythmic properties in several models of early and delayed afterdepolarization-related arrhythmias. Its effect on cardiac function was studied under intravenous infusion at 250,750 or 1500 µg/kg per hour in dogs, which were either normal or submitted to chronic ventricular pacing at 240 bpm (HF dogs). HF dogs were infused with the reference inotrope dobutamine (10 µg/kg per minute, i.v.). In normal dogs, NCX inhibitor increased cardiac contractility (dP/dtmax) and stroke volume (SV) and tended to reduce heart rate (HR). In HF dogs, NCX inhibitor significantly and dose-dependently increased SV from the first dose (+28.5%, +48.8%, and +62% at 250, 750, and 1500 µg/kg per hour, respectively) while significantly increasing dP/dtmax only at 1500 (+33%). Furthermore, NCX inhibitor significantly restored sympathovagal balance and spontaneous baroreflex sensitivity (BRS) from the first dose and reduced HR at the highest dose. In HF dogs, dobutamine significantly increased dP/dtmax and SV (+68.8%) but did not change HR, sympathovagal balance, or BRS. Overall, SAR340835, a selective potent NCX inhibitor, displayed a unique therapeutic profile, combining antiarrhythmic properties, capacity to restore systolic function, sympathovagal balance, and BRS in HF dogs. NCX inhibitors may offer new therapeutic options for acute HF treatment. SIGNIFICANCE STATEMENT: HF is facing growing health and economic burden. Moreover, patients hospitalized for acute heart failure are at high risk of decompensation recurrence, and no current acute decompensated HF therapy definitively improved outcomes. A new potent, Na+/Ca2+ exchanger inhibitor SAR340835 with antiarrhythmic properties improved systolic function of failing hearts without creating hypotension, while reducing heart rate and restoring sympathovagal balance. SAR340835 may offer a unique and attractive pharmacological profile for patients with acute heart failure as compared with current inotrope, such as dobutamine.


Subject(s)
Heart Failure/drug therapy , Membrane Transport Modulators/therapeutic use , Sodium-Calcium Exchanger/antagonists & inhibitors , Vagus Nerve/drug effects , Animals , Baroreflex , Dogs , Heart/drug effects , Heart Rate , Membrane Transport Modulators/administration & dosage , Membrane Transport Modulators/pharmacology , Myocardial Contraction , Myocardium/metabolism , Swine
2.
Cardiovasc Res ; 116(2): 329-338, 2020 02 01.
Article in English | MEDLINE | ID: mdl-31038167

ABSTRACT

AIMS: Despite improvements in patient identification and management, heart failure (HF) remains a major public health burden and an important clinical challenge. A variety of animal and human studies have provided evidence suggesting a central role of calcium/calmodulin-dependent protein kinase II (CaMKII) in the development of pathological cardiac remodelling and HF. Here, we describe a new potent, selective, and orally available CaMKII inhibitor. METHODS AND RESULTS: Chemical optimization led to the identification of RA306 as a selective CaMKII inhibitor. This compound was found potent on the cardiac CaMKII isoforms delta and gamma (IC50 in the 10 nM range), with pharmacokinetic properties allowing oral administration in animal models of HF. RA306 was administered to diseased mice carrying a mutation in alpha-actin that is responsible for dilated cardiomyopathy (DCM) in humans. In two separate studies, RA306 was orally administered at 30 mg/kg either for 2 weeks (twice a day) or for 2 months (once a day). Echocardiography monitoring showed that RA306 significantly improved cardiac function (ejection fraction and cardiac output) as compared to vehicle. These disease modifying effects of RA306 were associated with inhibition of cardiac phosphorylation of phospholamban (PLN) at threonine-17, indicating reduced cardiac CaMKII activity. CONCLUSION: This work supports the feasibility of identifying potent orally available CaMKII inhibitors suitable for clinical use to treat heart disease.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Cardiomyopathy, Dilated/drug therapy , Morpholines/administration & dosage , Myocytes, Cardiac/drug effects , Protein Kinase Inhibitors/administration & dosage , Stroke Volume/drug effects , Ventricular Function, Left/drug effects , Actins/genetics , Administration, Oral , Animals , Calcium-Binding Proteins/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cardiomyopathy, Dilated/enzymology , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/physiopathology , Cells, Cultured , Disease Models, Animal , Genetic Predisposition to Disease , Humans , Mice, Transgenic , Morpholines/pharmacokinetics , Mutation , Myocytes, Cardiac/enzymology , Phosphorylation , Protein Kinase Inhibitors/pharmacokinetics , Rats , Recovery of Function
3.
Bioorg Med Chem ; 17(6): 2607-22, 2009 Mar 15.
Article in English | MEDLINE | ID: mdl-19261477

ABSTRACT

Based on the definition of a 5-HT(4) receptor antagonist pharmacophore, a series of pyrrolo[1,2-a]thieno[3,2-e] and pyrrolo[1,2-a]thieno[2,3-e] pyrazine derivatives were designed, prepared, and evaluated to determine the properties necessary for high-affinity binding to 5-HT(4) receptors. The compounds were synthesized by substituting the chlorine atom of the pyrazine ring with various N-alkyl-4-piperidinylmethanolates. They were evaluated in binding assays with [(3)H]GR113808 (1) as the 5-HT(4) receptor radioligand. The affinity values (K(i) or inhibition percentages) were affected by both the substituent on the aromatic ring and the substituent on the lateral piperidine chain. A methyl group on the tricyclic ring produced a marked increase in affinity while an N-propyl or N-butyl group gave compounds with nanomolar affinities. Among the most potent ligands, 34d was selected for further pharmacological studies and evaluated in vivo. This compound acts as an antagonist/weak partial agonist in COS-7 cells stably expressing the 5-HT(4(a)) receptor and is of great interest as a peripheral antinociceptive agent.


Subject(s)
Pyrazines/chemical synthesis , Pyrazines/pharmacology , Serotonin 5-HT4 Receptor Antagonists , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Animals , COS Cells , Chlorocebus aethiops , Humans , Indoles/metabolism , Models, Molecular , Molecular Structure , Pyrazines/metabolism , Radioligand Assay , Serotonin Antagonists/metabolism , Sulfonamides/metabolism
4.
J Chem Inf Comput Sci ; 42(4): 962-7, 2002.
Article in English | MEDLINE | ID: mdl-12132898

ABSTRACT

A definition of a pharmacophore for the 5-HT4 antagonist was carried out by considering a three-dimensional model which correlates the chemical structures of series of antagonists with their biological affinities. A molecular design is described by analyzing the differences between two 3D serotonin pharmacophores. This successful structural modification demonstrates the efficiency of this approach to design new serotonin ligands.


Subject(s)
Computer Simulation , Drug Design , Receptors, Serotonin/drug effects , Computer-Aided Design , Ligands , Models, Chemical , Quantitative Structure-Activity Relationship , Receptors, Serotonin, 5-HT4 , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Software
5.
J Chem Inf Comput Sci ; 42(2): 429-36, 2002.
Article in English | MEDLINE | ID: mdl-11911713

ABSTRACT

A first definition of a pharmacophore for the serotonin reuptake inhibitors was carried out by considering a three-dimensional model which correlates the chemical structures of series of reuptake inhibitors with their biological affinities. A molecular design was described by analyzing two different 3D serotonin pharmacophores. This successful approach enabled us to consider the design of new serotonin ligands by the same method.


Subject(s)
Drug Design , Receptors, Serotonin/classification , Selective Serotonin Reuptake Inhibitors/chemistry
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