RESUMO
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.
Assuntos
Fármacos Antiobesidade/farmacologia , Benzodiazepinas/farmacologia , Indóis/farmacologia , Obesidade/tratamento farmacológico , Receptor de Colecistocinina A/agonistas , Tiazóis/farmacologia , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Quimiocinas CC , Humanos , Indóis/síntese química , Indóis/química , Metilaminas/síntese química , Metilaminas/química , Metilaminas/farmacologia , Camundongos , Piperazina , Piperazinas/química , Receptores da Colecistocinina/agonistas , Receptores da Colecistocinina/química , Tiazóis/síntese química , Tiazóis/químicaRESUMO
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.