title: C17,20-lyase inhibitors I. Structure-based de novo design and SAR study of C17,20-lyase inhibitors.
abstract: Novel nonsteroidal C(17,20)-lyase inhibitors were synthesized using de novo design based on its substrate, 17 alpha-hydroxypregnenolone, and several compounds exhibited potent C(17,20)-lyase inhibition. However, in vivo activities were found to be short-lasting, and in order to improve the duration of action, a series of benzothiophene derivatives were evaluated. As a result, compounds 9h, (S)-9i, and 9k with nanomolar enzyme inhibition (IC(50)=4-9 nM) and 9e (IC(50)=27 nM) were identified to have powerful in vivo efficacy with extended duration of action. The key structural determinants for the in vivo efficacy were demonstrated to be the 5-fluoro group on the benzothiophene ring and the 4-imidazolyl moiety. Superimposition of 9k and 17 alpha-hydroxypregnenolone demonstrated their structural similarity and enabled rationalization of the pharmacological results. In addition, selected compounds were also identified to be potent inhibitors of human enzyme with IC(50) values of 20-30 nM.
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division: Takeda Chemical Industries, Ltd, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. matsunaga_nobuyuki@takeda.ac.jp
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kaku
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Takahito
authors.initials: T
authors.lastname: Hara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Iwasaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Aono
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; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008861:Microsomes / Q000201:enzymology; D051381:Rats; D013055:Spectrophotometry, Infrared; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D013254:Steroid 17-alpha-Hydroxylase