Benzimidazole-5-sulfonamides as novel nonpeptide luteinizing hormone releasing hormone (LHRH) antagonists: minimization of mechanism-based CYP3A4 inhibition

Chem Pharm Bull (Tokyo). 2005 Oct;53(10):1314-7. doi: 10.1248/cpb.53.1314.

Abstract

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.

MeSH terms

  • Animals
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / pharmacology*
  • CHO Cells
  • Cricetinae
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Drug Evaluation, Preclinical
  • Gonadotropin-Releasing Hormone / antagonists & inhibitors*
  • Humans
  • Molecular Structure
  • Receptors, LHRH / antagonists & inhibitors
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Cytochrome P-450 Enzyme Inhibitors
  • Receptors, LHRH
  • Gonadotropin-Releasing Hormone
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human