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
2005 Chemical and pharmaceutical bulletin  
Part of the effort to reduce attrition rates in drug discovery and development is the early detection of CYP inhibition. 1) Irreversible (mechanism-based) CYP inhibitors inhibit CYP activity through chemical modifications of the enzyme, for instance through reactive metabolites. [2] [3] [4] In these cases, enzyme activity cannot be recovered by the removal of inhibitors. Potentially leading to liver toxicity, these compounds are unfavorable drug candidates and often avoided in drug discovery
more » ... n drug discovery and development. It is crucial to identify this undesired property at early stages in order to improve this parameter during lead optimisation. 5, 6) In previous communications we reported the discovery of potent non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists 1 and 2 ( Fig. 1 ) as possible therapeutics for the treatment of sex hormone-dependent disease states. 7,8) However, both compounds are plagued by time-dependent CYP3A4 inhibition that we wished to address early in the optimization process. In this report we would like to disclose SAR studies that led to the discovery of derivatives with optimized CYP3A4 profile and maintained potency. Chemistry Benzimidazoles 7, 10, 11, 14-18, and 22, 23 were prepared with benzylamines and tert-butyl isocyanates using methods described in previous communication. 8) The intermediates 7 were subjected to Sandmeyer reactions 9) in the presence of SO 2 /HCl to prepare the sulfonylchloride derivatives 8 which were reacted with various substituted benzylamines to prepare the corresponding sulfonamides 12, 13 and 19-21. Results and Discussion Compounds 1 and 2 both show increased CYP3A4 inhibition after incrementing preincubation times (Fig. 1) . This is also reflected by their strong inactivation constant (e.g. 2, k inact ϭ0.074 min Ϫ1 ). To rule out the possibility of mere product inhibition, we diluted the microsomal assay system 50 fold after preincubation. However, 2's CYP3A4 kinetics remained unchanged, also after dilution (k inact ϭ0.067 min Ϫ1 ). These findings confirmed the suspicion that our compounds would irreversibly inhibit CYP3A4, possibly via a reactive or chelating metabolite. 10) To gain insight into the metabolic fate of our compounds 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.
doi:10.1248/cpb.53.1314 pmid:16204990 fatcat:eu7kzre6ubgxbdwklwap72pieq