RESUMO
We describe the design, synthesis, and structure-activity relationships of triazolobenzodiazepinone CCK1 receptor agonists. Analogs in this series demonstrate potent agonist activity as measured by in vitro and in vivo assays for CCK1 agonism. Our efforts resulted in the identification of compound 4a which significantly reduced food intake with minimal systemic exposure in rodents.
Assuntos
Fármacos Antiobesidade/farmacologia , Benzodiazepinas/farmacologia , Receptores da Colecistocinina/agonistas , Animais , Fármacos Antiobesidade/farmacocinética , Benzodiazepinas/química , Benzodiazepinas/farmacocinética , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of 2-heteroaryl-4-arylimidazoles with potent in vitro activity at the NPY5 receptor was developed. Introduction of electron-withdrawing groups on the 4-aryl ring led to a significant improvement of in vitro potency. Several analogues from this series had anorectic activity in rodent feeding models, but were also found to have undesired behavioral effects in spontaneous locomotor activity.
Assuntos
Imidazóis/química , Imidazóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
Beginning with carbazole 1a, the amide and alkyl substituents were optimized to maintain potency while adding solubilizing groups. Efforts to replace the 3-amino-9-ethylcarbazole core, a known carcinogen, used the SAR generated in the carbazole series for guidance and led to the synthesis of a number of core-modified analogues. In addition, an isosteric series, in which the amide was replaced with an imidazole, was prepared. Two potent new series lacking the putative toxicophore were identified from these endeavors.