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.
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.
Matsunaga
Nobuyuki
N
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
Kaku
Tomohiro
T
Ojida
Akio
A
Tanaka
Toshimasa
T
Hara
Takahito
T
Yamaoka
Masuo
M
Kusaka
Masami
M
Tasaka
Akihiro
A
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
D004791:Enzyme Inhibitors; D007093:Imidazoles; D013739:Testosterone; D008190:Lyases