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
A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.
Subject(s)
Janus Kinase 3/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Autoimmune Diseases/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Immunity/drug effects , Janus Kinase 2/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.
