title: Epristeride is a selective and specific uncompetitive inhibitor of human steroid 5 alpha-reductase isoform 2.
abstract: Specificity of an enzyme inhibitor can have profound implications upon the compound's therapeutic potential, utility and safety profile. As potent inhibitors of human steroid 5 alpha-reductase (SR) the 3-androstene-3-carboxylic acids, or steroidal acrylates, may be useful in treatment of diseases such as benign prostatic hyperplasia for which 5 alpha-dihydrotestosterone (DHT) appears to be a causative agent. To determine its specificity profile, the interactions of a representative compound from this class, N-(t-butyl)androst-3,5-diene-17 beta-carboxamide-3-carboxylic acid (epristeride, SK&F 105657), have been studied with 7 other steroid processing enzymes and 5 steroid hormone receptors. The affinity of epristeride for each of these 12 potential targets was found to be at least 1000-fold weaker than that for SR, the intended target. In addition, using samples of the individually expressed two known forms of human SRs, epristeride has been shown to be a selective inhibitor of the recombinant human SR type 2, the predominant activity found in the prostate of man. Nonetheless, the mechanisms of SR inhibition for both isoenzymes involve formation of a ternary complex with epristeride, NADP+, and enzyme. Epristeride, consequently, has been shown to be an uncompetitive inhibitor versus steroid substrate of both human SR isoenzymes. These results suggest that this 3-androstene-3-carboxylic acid is a specific and selective inhibitor of the human type 2 SR, and that epristeride is an attractive compound for further investigation as a safe and effective therapeutic agent in the potential treatment of disease states associated with DHT-induced tissue growth.
authors.affiliation: Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
authors.forename: M A
authors.initials: MA
authors.lastname: Levy
authors.forename: M
authors.initials: M
authors.lastname: Brandt
authors.forename: K M
authors.initials: KM
authors.lastname: Sheedy
authors.forename: J T
authors.initials: JT
authors.lastname: Dinh
authors.forename: D A
authors.initials: DA
authors.lastname: Holt
authors.forename: L M
authors.initials: LM
authors.lastname: Garrison
authors.forename: D J
authors.initials: DJ
authors.lastname: Bergsma
authors.forename: B W
authors.initials: BW
authors.lastname: Metcalf
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000730:Androstadienes / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D008297:Male; D009249:NADP / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
chemical_list: D058891:5-alpha Reductase Inhibitors; D000730:Androstadienes; D007527:Isoenzymes; D011994:Recombinant Proteins; C072547:epristeride; D009249:NADP; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase