title: Benzimidazole-5-sulfonamides as novel nonpeptide luteinizing hormone releasing hormone (LHRH) antagonists: minimization of mechanism-based CYP3A4 inhibition.
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.
authors.affiliation: Research Center Kyoto, Bayer Yakuhin, Ltd., Kyoto, Japan. kentaro.hashimoto@bayerhealthcare.com
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Mikayo
authors.initials: M
authors.lastname: Kataoka
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tatsuta
authors.forename: Kayo
authors.initials: K
authors.lastname: Yasoshima
authors.forename: Mako
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yura
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Klaus
authors.initials: K
authors.lastname: Urbahns
authors.forename: Jang Bahadur
authors.initials: JB
authors.lastname: Gupta
authors.forename: Yingfu
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004353:Drug Evaluation, Preclinical; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human