title: 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 by 6-azaandrost-4-en-3-ones: optimization of the C17 substituent.
abstract: A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared 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) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.
authors.affiliation: Glaxo Inc. Research Institute, Research Triangle Park, North Carolina 27709, USA.
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 N
authors.initials: RN
authors.lastname: Hiner
authors.forename: G F
authors.initials: GF
authors.lastname: Dorsey
authors.forename: R A
authors.initials: RA
authors.lastname: Noe
authors.forename: R J
authors.initials: RJ
authors.lastname: Unwalla
authors.forename: K W
authors.initials: KW
authors.lastname: Batchelor
authors.forename: H N
authors.initials: HN
authors.lastname: Bramson
authors.forename: J D
authors.initials: JD
authors.lastname: Stuart
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 / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D006801:Humans; D008297:Male; D008958:Models, Molecular; 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; D015096:3-Hydroxysteroid Dehydrogenases; D013251:Steroid Isomerases; C022660:steroid delta-isomerase