ABSTRACT
The discovery and structure-activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight food intake reduction assay.
Subject(s)
Anti-Obesity Agents/pharmacology , Benzodiazepines/pharmacology , Indoles/pharmacology , Obesity/drug therapy , Receptor, Cholecystokinin A/agonists , Thiazoles/pharmacology , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/chemistry , Benzodiazepines/chemical synthesis , Benzodiazepines/chemistry , Chemokines, CC , Humans , Indoles/chemical synthesis , Indoles/chemistry , Methylamines/chemical synthesis , Methylamines/chemistry , Methylamines/pharmacology , Mice , Piperazine , Piperazines/chemistry , Receptors, Cholecystokinin/agonists , Receptors, Cholecystokinin/chemistry , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
High-throughput screening revealed diaryl pyrazole 3 as a selective albeit modest cholecystokinin 1 receptor (CCK1R) agonist. SAR studies led to the discovery and optimization of a novel class of 1,2-diaryl imidazole carboxamides. Compound 44, which was profiled extensively, showed good in vivo mouse gallbladder emptying (mGBE) and lean mouse overnight food intake (ONFI) reduction activities.