EPRISTERIDE IS A SELECTIVE AND SPECIFIC UNCOMPETITIVE INHIBITOR OF HUMAN STEROID 5-ALPHA-REDUCTASE ISOFORM-2

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 5alpha-reductase (SR) the 3-androst ene-3-carboxylic acids, or steroidal acrylates, may be useful in treat ment of diseases such as benign prostatic hyperplasia for which 5alpha -dihydrotestosterone (DHT) appears to be a causative agent. To determi ne its specificity profile, the interactions of a representative compo und from this class, )androst-3,5-diene-17beta-carboxamide-3-carboxyli c acid (epristeride, SK&F 105657), have been studied with 7 other ster oid processing enzymes and 5 steroid hormone receptors. The affinity o f epristeride for each of these 12 potential targets was found to be a t least 1000-fold weaker than that for SR, the intended target. In add ition, using samples of the individually expressed two known forms of human SRs, epristeride has been shown to be a selective inhibitor of t he 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, N ADP+, and enzyme. Epristeride, consequently, has been shown to be an u ncompetitive inhibitor versus steroid substrate of both human SR isoen zymes. 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 dis ease states associated with DHT-induced tissue growth.