ABSTRACT
A study that was designed to identify plausible replacements for highly basic guanidine moiety contained in potent MC4R agonists, as exemplified by 1, led to the discovery of initial nonguanidine lead 5. Propyl analog 23 was subsequently found to be equipotent to 5, whereas analogs bearing smaller and branched alkyl groups at the 3 position of the oxopiperazine template demonstrated reduced binding affinity and agonist potency for MC4R. Acylation of the NH2 group of the 4F-D-Phe residue of 3-propyl analog 23 significantly increased the binding affinity and the functional activity for MC4R. Analogs with neutral and weakly basic capping groups of the D-Phe residue exhibited excellent MC4R selectivity against MC1R whereas those with an amino acid had moderate MC4R/MC1R selectivity. We have also demonstrated that compound 35 showed promising oral bioavailability and a moderate oral half life and induced significant weight loss in a 28-day rat obesity model.
Subject(s)
Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/therapeutic use , Obesity/drug therapy , Piperazines/pharmacology , Piperazines/therapeutic use , Receptor, Melanocortin, Type 4/agonists , Administration, Oral , Animals , Anti-Obesity Agents/chemistry , Biological Availability , Diet , Disease Models, Animal , Dogs , Drug Design , Drug Evaluation, Preclinical , Eating/drug effects , Male , Molecular Conformation , Piperazines/chemistry , Rats , StereoisomerismABSTRACT
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.
