title: Indole derivatives as a new class of steroid 5 alpha-reductase inhibitors.
abstract: A series of indole derivatives with varied substituents on the alpha, beta-unsaturated double bond were synthesized and evaluated for their ability to inhibit rat prostatic 5 alpha-reductase. Compounds possessing an ethyl substituent at the beta-position of the double bond showed potent inhibitory activity. Among them, (Z)-4-{2-[[3-[1-(4,4'-difluorobenzhydryl)indol-5-yl]-2-pentenoy l]- amino]phenoxy}butyric acid (16, KF20405) showed the maximum potency with an IC50 value of 0.48 +/- 0.086 nM, which was 20-fold higher potency than 1 (MK-906). Compound 16 effectively inhibited DHT production 4 h after a 3 mg/kg oral administration. Several potent indole derivatives, 1 and 2 ((+/-)-ONO-3805), were tested versus rat and human isozymes. Nonsteroidal inhibitors such as indole derivatives and 2 were 2-3 orders of magnitude less potent for human type 2 isozyme than steroidal inhibitor 1 and expressed a significant species deference for these isozymes.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takami
authors.forename: H
authors.initials: H
authors.lastname: Koshimura
authors.forename: N
authors.initials: N
authors.lastname: Kishibayashi
authors.forename: A
authors.initials: A
authors.lastname: Ishii
authors.forename: H
authors.initials: H
authors.lastname: Nonaka
authors.forename: S
authors.initials: S
authors.lastname: Aoyama
authors.forename: H
authors.initials: H
authors.lastname: Kase
authors.forename: T
authors.initials: T
authors.lastname: Kumazawa
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011467:Prostate / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes