title: 17,20-Lyase inhibitors. Part 3: Design, synthesis, and structure-activity relationships of biphenylylmethylimidazole derivatives as novel 17,20-lyase inhibitors.
abstract: A novel series of biphenylylmethylimidazole derivatives and related compounds were synthesized as inhibitors of 17,20-lyase, a key enzyme in the production of steroid hormones, and their biological activities were evaluated. In an attempt to identify potent and selective inhibitors of 17,20-lyase over the related CYP3A4 enzyme, a homology model for human 17,20-lyase was developed using the X-ray crystallographic structure of the mammalian CYP2C5 enzyme. With the aid of molecular modeling, optimization of the biphenyl moiety was performed to give an acetamide derivative, which was resolved by HPLC to give the active (-)-enantiomer. The obtained active enantiomer showed not only potent inhibition of both rat and human 17,20-lyase,with IC(50) values of 14 and 26 nM, respectively, but also excellent selectivity (>300-fold) for inhibition of 17,20-lyase over CYP3A4. Moreover, the active enantiomer significantly reduced both serum testosterone and DHEA concentrations in a monkey model after single oral administration. Asymmetric synthesis of the active enantiomer was also developed via a chiral intermediate using a diastereoselective Grignard reaction.
authors.affiliation: Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Company, Ltd, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. Kaku_Tomohiro@takeda.co.jp
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kaku
authors.forename: Saori
authors.initials: S
authors.lastname: Tsujimoto
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Takahito
authors.initials: T
authors.lastname: Hara
authors.forename: Masuo
authors.initials: M
authors.lastname: Yamaoka
authors.forename: Masami
authors.initials: M
authors.lastname: Kusaka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tasaka
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008252:Macaca fascicularis; D008297:Male; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D051544:Cytochrome P-450 CYP3A; D013254:Steroid 17-alpha-Hydroxylase; C510163:CYP3A4 protein, human