Novel nonsteroidal inhibitor of cytochrome P450(17alpha) (17alpha-hydroxylase/C17-20 lyase), YM116, decreased prostatic weights by reducing serum concentrations of testosterone and adrenal androgens in rats

Background: The purpose of this study was to determine the effects of a nonsteroidal C17-20 lyase inhibitor, 2-(1H-imidazol-4-ylmethyl)-9H-carbazole (YM116), on serum concentrations of androgens and ventral prostatic weight in rats.

Methods: Serum concentrations of testosterone and of dehydroepiandrosterone sulfate and prostatic weights were measured in rats treated with YM116.

Results: YM116 inhibited testicular C17-20 lyase competitively (Ki, 0.38 nM), and decreased the serum testosterone concentration in gonadotropin-releasing hormone-treated rats (ED50, 0.7 mg/kg), indicating that YM116 was about 21-24 times more potent than Other C17-20 lyase inhibitors such as ketoconazole and liarozole, and was twice as potent as CB7630. YM116 also reduced dehydroepiandrosterone sulfate levels in ACTH-treated castrated rats (ED50, 11 mg/kg). YM116 (40 mg/kg, p.o., for 2 weeks) was almost comparable to bilateral orchiectomy with respect to the time course and magnitude of the reduction in prostatic weight. Each of these two treatments decreased the prostatic weight 3 days following the treatment. Contrarily, leuprolide transiently increased the prostatic weight and then decreased it. YM116 (100 mg/kg) had no effect on the serum cortisol level in guinea pigs, and slightly decreased the serum aldosterone level in rats.

Conclusions: YM116 is a selective C17-20 lyase inhibitor which decreases rat prostatic weight by reducing androgen production in the testes and adrenal glands.