Naohiro Yasuda, Katsuhiro Fujino, Takamitsu Shiraji, Fumio Nambu and
Kigen Kondo
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