ABSTRACT
Despite the high number of drug-discovery programs dedicated to finding small-molecule MCH-R1 antagonists for the treatment of obesity and/or mood disorders, a very limited number of these have progressed into the clinic. Beyond the common challenges in drug design related to ADME and safety profiles, cardiovascular risk involving hERG binding and the potential for subsequent drug-induced QTc prolongation has been a major hurdle for a significant number of MCH-R1 research programs. Many of these programs have evolved, and effectively designed MCH antagonists having decreased hERG-binding affinity have emerged. Currently, however, only a selected few candidates have progressed to clinical development. Drug-design strategies, in vivo efficacy, ADME, and cardiovascular safety profiles for a selection of MCH-R1 antagonist research programs are discussed ahead.
Subject(s)
Drug Design , Mood Disorders/drug therapy , Obesity/drug therapy , Receptors, Somatostatin/antagonists & inhibitors , Animals , Clinical Trials as Topic , Humans , Structure-Activity RelationshipABSTRACT
The design, synthesis, and biological studies of a novel class of MCH-R1 antagonists based on an aminotetrahydronaphthalene ketopiperazine scaffold is described. Compounds within this class promoted significant body weight reduction in mouse diet induced obesity studies. The potential for hERG blockage activity and QT interval studies in anesthetized dogs are discussed.
Subject(s)
Piperazines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Animals , Dogs , Drug Evaluation, Preclinical , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Models, Molecular , Piperazines/chemistry , Structure-Activity RelationshipABSTRACT
Aminomethyl tetrahydronaphthalene biphenyl carboxamide MCH-R1 antagonists with greater selectivity over hERG were identified. SAR studies addressing two distinct alternatives for structural modifications leading to improve hERG selectivity are described.
Subject(s)
Biphenyl Compounds/pharmacology , Ether-A-Go-Go Potassium Channels/drug effects , Naphthalenes/pharmacology , Potassium Channel Blockers/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Biphenyl Compounds/chemical synthesis , ERG1 Potassium Channel , Ergolines/pharmacology , Humans , Indicators and Reagents , Mianserin/pharmacology , Naphthalenes/chemical synthesis , Receptor, Serotonin, 5-HT2C/drug effects , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
A direct correlation between hERG binding and QTc prolongation was established for a series of aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists. Compounds within this class with greater selectivity over hERG were developed. Compound 4h proved to have the best profile, with MCH-R1 Ki = 16 nm and hERG IC50 = 25 microM.
Subject(s)
Ether-A-Go-Go Potassium Channels/drug effects , Naphthalenes/pharmacology , Piperazines/pharmacology , Potassium Channel Blockers/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Animals , Dogs , ERG1 Potassium Channel , Heart Rate/drug effects , Humans , Indicators and Reagents , Mice , Naphthalenes/chemical synthesis , Piperazines/chemical synthesis , Weight Loss/drug effectsABSTRACT
A substituted 4-aminopiperidine was identified as showing activity in an MCH assay from an HTS effort. Subsequent structural modification of the scaffold led to the identification of a number of active MCH antagonists. 3,5-Dimethoxy-N-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)benzamide (5c) was among those with the highest binding affinity to the MCH receptor (K(i)=27nM), when variations were made at benzoyl and naphthylmethyl substitution sites from the initial HTS hit. Further optimization via piperidine ring contraction resulted in enhanced MCH activity in a 3-aminopyrrolidine series, where (R)-3,5-dimethoxy-N-(1-(naphthalen-2-ylmethyl)-pyrrolidin-3-yl)benzamide (10i) was found to be an excellent MCH antagonist (K(i)=7nM).
Subject(s)
Obesity/drug therapy , Piperidines/pharmacology , Piperidines/therapeutic use , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Receptors, Somatostatin/antagonists & inhibitors , Binding, Competitive/drug effects , Drug Evaluation, Preclinical , Humans , Molecular Structure , Piperidines/chemistry , Pyrrolidines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel series of substituted quinoline analogs were designed and synthesized as potent and selective melanin concentrating hormone (MCH) antagonists. These analogs show potent (nM) activity (12a-k) with a moderate selectivity. Conversely, the conformationally constrained thienopyrimidinone analogs (18a-g) showed improved activity in MCH-1R and selectivity over 5HT2C.
