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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.

chemical and pharmaceutical bulletin/chemical and pharmaceutical bulletin

Benzimidazole-5-sulfonamides as Novel Nonpeptide Luteinizing Hormone Releasing Hormone (LHRH) Antagonists: Minimization of Mechanism-Based CYP3A4 Inhibition