title: 6-Azasteroids: structure-activity relationships for inhibition of type 1 and 2 human 5 alpha-reductase and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase.
abstract: 6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar Ki's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.
authors.affiliation: Glaxo Inc. Research Institute, Research Triangle Park, North Carolina 27709.
authors.forename: S V
authors.initials: SV
authors.lastname: Frye
authors.forename: C D
authors.initials: CD
authors.lastname: Haffner
authors.forename: P R
authors.initials: PR
authors.lastname: Maloney
authors.forename: R A
authors.initials: RA
authors.lastname: Mook
authors.forename: G F
authors.initials: GF
authors.lastname: Dorsey
authors.forename: R N
authors.initials: RN
authors.lastname: Hiner
authors.forename: C M
authors.initials: CM
authors.lastname: Cribbs
authors.forename: T N
authors.initials: TN
authors.lastname: Wheeler
authors.forename: J A
authors.initials: JA
authors.lastname: Ray
authors.forename: R C
authors.initials: RC
authors.lastname: Andrews
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D058891:5-alpha Reductase Inhibitors; D000311:Adrenal Glands / Q000201:enzymology*; D000818:Animals; D001378:Azasteroids / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013251:Steroid Isomerases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D007527:Isoenzymes; D015096:3-Hydroxysteroid Dehydrogenases; C031954:delta(5)-3 beta-hydroxysteroid dehydrogenase; D013251:Steroid Isomerases; C022660:steroid delta-isomerase