title: (E)-4-(2-[[3-(indol-5-yl)-1-oxo-2-butenyl]amino]phenoxy)butyric acid derivatives: a new class of steroid 5 alpha-reductase inhibitors in the rat prostate. 1.
abstract: A series of (E)-4-(2-[[3-(indol-5-yl)-1-oxo-2-butenyl]amino]phenoxy)butyric acid derivatives was prepared, and the derivatives were demonstrated to be potent inhibitors of steroid 5 alpha-reductase in the rat prostate. The structure-activity relationships were as follows. An alpha-branched alkyl or benzyl substituent of proper size at position 1 of the indole is crucial for optimal enzyme inhibitory activity. N-Methylation of the amide NH resulted in complete loss of activity. Thus, coplanarity of the benzene ring and amide moiety is essential for such activity. Among the compounds prepared, (E)-4-(2-[[3-[1-[bis(4-fluorophenyl)methyl]indol-5-yl]-1-oxo-2- butenyl]-amino]phenoxy)butyric acid (57, KF18678) was one of the most potent compounds (rat prostate 5 alpha-reductase IC50 = 3.3 nM).
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kumazawa
authors.forename: H
authors.initials: H
authors.lastname: Takami
authors.forename: N
authors.initials: N
authors.lastname: Kishibayashi
authors.forename: A
authors.initials: A
authors.lastname: Ishii
authors.forename: Y
authors.initials: Y
authors.lastname: Nagahara
authors.forename: N
authors.initials: N
authors.lastname: Hirayama
authors.forename: H
authors.initials: H
authors.lastname: Obase
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000818:Animals; D002087:Butyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D011467:Prostate / Q000737:chemistry* / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D058891:5-alpha Reductase Inhibitors; D002087:Butyrates; D007211:Indoles