PNU 157706, A NOVEL DUAL TYPE-I AND TYPE-II 5-ALPHA-REDUCTASE INHIBITOR

PNU 157706 is a novel dual inhibitor of 5 alpha-reductase (5 alpha-R), the enzyme responsible for the conversion of testosterone (T) to 5 al pha-dihydrotestosterone (DHT). Tested on a crude preparation of human or rat prostatic 5 alpha-R, PNU 157706 caused enzyme inhibition with I C50 values of 20 and 34 nM, respectively, compared to the values of 32 and 58 nM shown by finasteride. Furthermore, PNU 157706 was highly po tent in inhibiting human recombinant 5 alpha-R type I and II isozymes, showing IC50 values of 3.9 and 1.8 nM and, therefore, it was several folds more potent than finasteride (IC50 values of 313 and 11.3 nM), p articularly on the type I isozyme. PNU 157706 was shown to have no bin ding affinity for the rat prostate androgen receptor (RBA 0.009% that of DHT). In adult male rats, a single oral dose of 10 mg/kg of PNU 157 706 caused a marked and longer lasting reduction of prostatic DHT than did finasteride (at 24 h inhibition by 89 and 47%, respectively). In prepubertal, T- or DHT-implanted castrated rats, PNU 157706, given ora lly for 7 days at the dose of 10 mg/kg/day, markedly reduced ventral p rostate weight in T-but not in DHT-implanted animals, thus showing to be devoid of any anti-androgen activity. In adult rats treated orally for 28 days, PNU 157706 resulted markedly more potent (16-fold) than f inasteride in reducing prostate weight, the ED50 values being 0.12 and 1.9 mg/kg/day, respectively. These results indicate that PNU 157706 i s a promising, potent inhibitor of both type II and I human 5 alpha-R with a very marked antiprostatic effect in the rat. (C) 1998 Elsevier Science Ltd. All rights reserved.