RESUMO
A series of pyrrolopyridinones was designed and synthesized as constrained analogs of the pyrazole CB-1 antagonist rimonabant. Certain examples exhibited very potent hCB-1 receptor binding affinity and functional antagonism with Ki and Kb values below 10 nM, and with high selectivity for CB-1 over CB-2 (>100-fold). A representative analog was established to cause significant appetite suppression and reduction in body weight gain in industry-standard rat models used to develop new therapeutics for obesity.
Assuntos
Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Piridonas/síntese química , Pirróis/síntese química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Peso Corporal/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Obesidade/tratamento farmacológico , Piridonas/farmacocinética , Piridonas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Ratos Wistar , Ratos Zucker , Rimonabanto , Relação Estrutura-Atividade , Aumento de Peso/efeitos dos fármacosRESUMO
Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 K(i)=3.7nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.