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.
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.
Asunto(s)
Pirrolidinas/química , Receptores de Progesterona/agonistas , Administración Oral , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Modelos Animales , Estructura Terciaria de Proteína , Pirrolidinas/administración & dosificación , Pirrolidinas/síntesis química , Ratas , Receptores de Progesterona/metabolismoRESUMEN
The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.
