title: C(17,20)-lyase inhibitors. Part 2: design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C(17,20)-lyase inhibitors.
abstract: A series of 1- and 4-(2-naphthylmethyl)-1H-imidazoles (3 and 4) has been synthesized and evaluated as C(17,20)-lyase inhibitors. Several 6-methoxynaphthyl derivatives showed potent C(17,20)-lyase inhibition, suppression of testosterone biosynthesis in rats and reduction in the weight of prostate and seminal vesicles in rats, whereas most of these compounds increased the liver weight after consecutive administrations. The effect on the liver weight was removed by incorporation of a hydroxy group and an isopropyl group at the methylene bridge, as seen in (S)-28d and (S)-42. Selectivity for C(17,20)-lyase over 11beta-hydroxylase is also discussed, and (S)-42 was found to be a more than 260-fold selective inhibitor. Furthermore, (S)-42 showed a potent suppression of testosterone biosynthesis after a single oral administration in monkeys. These data suggest that (S)-42 may be a promising agent for the treatment of androgen-dependent prostate cancer.
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.co.jp
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kaku
authors.forename: Akio
authors.initials: A
authors.lastname: Ojida
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; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D008190:Lyases / Q000037:antagonists & inhibitors*; D008297:Male; D008956:Models, Chemical; D011467:Prostate / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011485:Protein Binding; D051381:Rats; D012669:Seminal Vesicles / Q000187:drug effects; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000096:biosynthesis
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D013739:Testosterone; D008190:Lyases