ABSTRACT
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.
