RESUMEN
We have designed and synthesized a novel series of pyrrolidinones as progesterone receptor partial agonists. Compounds from this series had improved AR selectivity, rat pharmacokinetic properties, and in vivo potency compared to the lead compound. In addition, these compounds had improved selectivity against hERG channel inhibition.
Asunto(s)
Pirrolidinonas/química , Receptores de Progesterona/agonistas , Administración Oral , Animales , Sitios de Unión , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/metabolismo , Haplorrinos , Humanos , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacocinética , Ratas , Receptores de Progesterona/metabolismo , Relación Estructura-ActividadRESUMEN
Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.
