title: Inhibition of steroid 5 alpha-reductase by unsaturated 3-carboxysteroids.
abstract: A series of unsaturated steroids bearing a 3-carboxy substituent has been prepared and assayed in vitro as inhibitors of human and rat prostatic steroid 5 alpha-reductase (EC 1.3.1.30). It is proposed that the observed tight binding of the 3-androstene-3-carboxylic acids is due to mimicry of a putative, high-energy, enzyme-bound enolate intermediate formed during the NADPH-dependent conjugate reduction of testosterone by steroid 5 alpha-reductase. These compounds were prepared through palladium(0)-catalyzed carbomethoxylations of enol (trifluoromethyl)sulfonates derived from 3-keto precursors. Modification of A and B ring unsaturation and substitution at C-3, -4, -6, and -11 was explored. Mono- and dialkylcarboxamides were employed as 17 beta side chains to enhance inhibitory activity with the human enzyme.
authors.affiliation: Department of Medicinal Chemistry, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406.
authors.forename: D A
authors.initials: DA
authors.lastname: Holt
authors.forename: M A
authors.initials: MA
authors.lastname: Levy
authors.forename: H J
authors.initials: HJ
authors.lastname: Oh
authors.forename: J M
authors.initials: JM
authors.lastname: Erb
authors.forename: J I
authors.initials: JI
authors.lastname: Heaslip
authors.forename: M
authors.initials: M
authors.lastname: Brandt
authors.forename: H Y
authors.initials: HY
authors.lastname: Lan-Hargest
authors.forename: B W
authors.initials: BW
authors.lastname: Metcalf
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008297:Male; D011467:Prostate / Q000201:enzymology; D051381:Rats; D013256:Steroids / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D058891:5-alpha Reductase Inhibitors; D002264:Carboxylic Acids; D013256:Steroids