Naohiro Yasuda, Katsuhiro Fujino, Takamitsu Shiraji, Fumio Nambu and
Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1, Sakurai Shimamoto-cho, Mishima-gun, Osaka 618, Japan
Abstract: ONO-9302 [epristeride; (-)-17beta-(tert-butylcarbamoyl)androsta-3,5-diene-3-carboxylic acid] is a novel inhibitor of steroid 5alpha-reductase. We studied in vitro and in vivo effects of ONO-9302 on the rat prostatic tissue in comparison with those of the anti-androgen allylestrenol. ONO-9302 inhibited the rat prostatic enzyme with an IC50 value of 11 nM, whereas allylestrenol was about 80,000-fold less potent. The growth of ventral prostate, which was induced by the subcutaneous injection of testosterone propionate in the castrated rats, was significantly reduced by ONO-9302 at oral doses of 1 - 100 mg/kg/day. Allylestrenol showed a significant effect only at a dose of 100 mg/kg/day. In mature male rats, ONO-9302 significantly reduced the ventral prostate weight at doses of 10 - 100 mg/kg/day and decreased prostatic 5alpha-dihydrotestosterone (DHT) content associated with a rise in testosterone (T) content at doses of 0.1 - 100 mg/kg/day. Plasma hormone levels (i.e., T, DHT, luteinizing hormone (LH) and follicle stimulating hormone (FSH)) were not altered significantly. Allylestrenol significantly reduced the ventral prostate weight at doses of 10 - 100 mg/kg/day. However, unlike ONO-9302, allylestrenol reduced both the prostatic DHT and T contents and also lowered plasma T, DHT, LH and FSH levels at a dose of 30 mg/kg/day. These results suggest that ONO-9302 reduces the prostatic growth by inhibiting the conversion of T to DHT in the prostate without lowering blood T level unlike anti-androgen drugs.
Keywords: Steroid 5alpha-reductase, Dihydrotestosterone, Testosterone, Prostate, ONO-9302