RESUMO
The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB(1) antagonist with high predicted human oral bioavailability.
Assuntos
Indóis/farmacocinética , Receptor CB1 de Canabinoide/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Humanos , Indóis/administração & dosagem , Indóis/química , Relação Estrutura-AtividadeRESUMO
The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist.
Assuntos
Amidas/química , Indóis/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Indóis/síntese química , Indóis/farmacocinética , Masculino , Camundongos , Modelos Moleculares , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.