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

Notes

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

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Keywords: luteinizing hormone releasing hormone (LHRH), antagonist, irreversible CYP3A4 inhibition, mechanism-based, small molecule

JOURNAL FREE ACCESS

2005 Volume 53 Issue 10 Pages 1314-1317

DOI https://doi.org/10.1248/cpb.53.1314

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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.

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