RESUMEN

A series of potent indolyl azetidine rMCHR1 antagonists were found to show poor CNS penetration due to Pgp efflux. We envisioned a strategy which included: lowering basicity; changing the conformational flexibility motif; and removal of a hydrogen bond donor, in an attempt to optimize this property while maintaining target receptor efficacy. This work resulted in mitigation of Pgp efflux, and led us to identify 1-dihydroindolyl azetidine derivatives with CNS penetration and excellent rMCHR1 binding affinity.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Azetidinas/farmacología , Indoles/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/deficiencia , Animales , Azetidinas/síntesis química , Azetidinas/química , Enlace de Hidrógeno , Indoles/síntesis química , Indoles/química , Ratones , Ratones Noqueados , Estructura Molecular , Ratas , Receptores de Somatostatina/metabolismo , Estereoisomerismo