RESUMEN
Herein we report the development of novel, potent and non-peptide luteinizing hormone releasing hormone (LHRH) antagonists. The optimization towards derivatives free from mechanism-based CYP3A4 inhibition is described. The identification of a main metabolite guided us towards structural modifications of the benzyl moiety, which resulted in significant improvements of the CYP3A4 profile, while maintaining potent LHRH antagonist activity.
Asunto(s)
Bencimidazoles/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Animales , Bencimidazoles/síntesis química , Células CHO , Cricetinae , Citocromo P-450 CYP3A , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Receptores LHRH/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
1-(1H-Benzimidazol-5-yl)-3-tert-butylurea derivatives have been identified as a novel class of non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists. Herein, we disclose the synthesis and structure-activity relationships (SAR) of this class resulting in the identification of compound 12c, with dual functional activity on human and rat receptors (rat LHRH: IC50=120 nM; human LHRH: IC50=18 nM). These SAR studies suggest that 1-(1H-benzimidazol-5-yl)-3-tert-butylurea is a new pharmacophore for small molecule LHRH antagonists.
Asunto(s)
Bencimidazoles/farmacología , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Bencimidazoles/síntesis química , Humanos , Cinética , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacologíaRESUMEN
A new class of benzimidazole-5-sulfonamides has been identified as nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists. Initial structure-activity relationships are presented resulting in compounds 19 and 28 with submicromolar dual functional activity on human and rat receptors.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Animales , Humanos , Concentración 50 Inhibidora , Ligandos , Ratas , Relación Estructura-ActividadRESUMEN
The 2-cyclopropyl substituted benzimidazole 2 has been used as a starting point for further optimization of an LHRH antagonist series. SAR studies revealed that a tert-butyl urea fragment connected through a simple carbon chain would improve activity. Further modification of the benzylsulfonamide moiety led to the discovery of 23 (IC(50): 4.2 nM).