RESUMEN
A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.
Asunto(s)
Anabolizantes/síntesis química , Imidazoles/síntesis química , Músculo Esquelético/efectos de los fármacos , Pirroles/síntesis química , Receptores Androgénicos/metabolismo , Administración Oral , Anabolizantes/farmacocinética , Anabolizantes/farmacología , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Semivida , Imidazoles/farmacocinética , Imidazoles/farmacología , Masculino , Modelos Moleculares , Músculo Esquelético/anatomía & histología , Orquiectomía , Próstata/anatomía & histología , Próstata/efectos de los fármacos , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.