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

Kentaro Hashimoto; Mikayo Kataoka; Miyuki Tatsuta; Kayo Yasoshima; Mako Yamamoto; Takeshi Yura; Noriyuki Yamamoto; Klaus Urbahns; Jang Bahadur Gupta; Yingfu Li

doi:10.1248/cpb.53.1314

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.

Authors

Kentaro Hashimoto¹, Mikayo Kataoka, Miyuki Tatsuta, Kayo Yasoshima, Mako Yamamoto, Takeshi Yura, Noriyuki Yamamoto, Klaus Urbahns, Jang Bahadur Gupta, Yingfu Li

Affiliation

¹ Research Center Kyoto, Bayer Yakuhin, Ltd., Kyoto, Japan. [email protected]

PMID: 16204990
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