RESUMEN
The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.
Asunto(s)
Pirrolidinas/química , Receptores de Progesterona/agonistas , Animales , Sitios de Unión , Carbamatos/química , Cristalografía por Rayos X , Canal de Potasio ERG1 , Endometriosis/tratamiento farmacológico , Canales de Potasio Éter-A-Go-Go/metabolismo , Femenino , Humanos , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Ratas , Receptores de Progesterona/metabolismo , Sulfonamidas/químicaRESUMEN
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.