RESUMEN
Mifepristone is a non-selective antagonist of 3-oxosteroid receptors with both abortifacient and anti-diabetic activities. For glucocorticoid receptor (GR) program, we sought an unexplored, synthetically accessible phosphorus-containing steroidal mimetic of mifepristone, suitable for parallel synthesis of analogues. One compound 4a, with high oral bioavailability (59%) in rat, exhibited functional antagonism of GR in oral glucose tolerance test (OGTT). Thus this series of compounds might be potentially useful for the treatment of type II diabetes.
Asunto(s)
Fósforo , Receptores de Glucocorticoides/antagonistas & inhibidores , Esteroides/síntesis química , Esteroides/farmacocinética , Animales , Disponibilidad Biológica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Prueba de Tolerancia a la Glucosa , Humanos , Concentración 50 Inhibidora , Mifepristona/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A series of novel 2-(1H-indol-2-yl)-propan-2-ols have been designed, synthesized, and screened for their ability to inhibit testosterone-induced prostate weight increases in immature rats. Through the use of this paradigm, we were able to identify compounds that exhibited in vivo potency equal to that of the marketed antiandrogen Casodex when orally administered.
Asunto(s)
Antagonistas de Andrógenos/química , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores Androgénicos , Indoles/química , Indoles/farmacología , Próstata/efectos de los fármacos , Administración Oral , Antagonistas de Andrógenos/síntesis química , Anilidas/farmacología , Animales , Evaluación Preclínica de Medicamentos/métodos , Indoles/síntesis química , Masculino , Nitrilos/farmacología , Ratas , Relación Estructura-Actividad , Compuestos de Tosilo/farmacologíaRESUMEN
A novel series of steroidal compounds were designed and synthesized with various phosphorus-containing groups on the 17beta-side chain as progesterone receptor antagonists. The structure-activity relationships of these compounds are discussed. Selected compounds were tested in an rat progesterone-sensitive assay. Some of these compounds are more potent than mifepristone, with a better selectivity profile in differentiating progesterone receptor from glucocorticoid receptor.