RESUMEN
Based on SAR from bicyclic GnRH antagonists such as 6-aminomethyl-7-arylpyrrolo[1,2-a]pyrimid-4-ones (1) and 2-aryl-3-aminomethylimidazolo[1,2-a]pyrimid-5-ones (2a,b), a series of novel uracil compounds (4) were derived as the GnRH antagonists. Their syntheses and initial SAR are discussed herein. This is the first time that monocycle-based GnRH receptor antagonists are reported.
Asunto(s)
Imidazoles/síntesis química , Pirroles/síntesis química , Receptores LHRH/antagonistas & inhibidores , Uracilo/síntesis química , Animales , Estabilidad de Medicamentos , Humanos , Imidazoles/química , Imidazoles/farmacología , Técnicas In Vitro , Tasa de Depuración Metabólica , Ratones , Microsomas Hepáticos/metabolismo , Pirroles/química , Pirroles/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Uracilo/química , Uracilo/farmacologíaRESUMEN
Uracils possessing N-3 side chains derived from various amino alcohols were designed and synthesized as potent human gonadotropin releasing hormone receptor antagonists. The compounds herein presented displayed superior metabolic stability than their predecessor molecules. Selected compounds from this series featured good oral bioavailability in mice and cynomolgus monkeys.