Novel nonsteroidal inhibitor of cytochrome P45017 (17α‐hydroxylase/C17–20 lyase), YM116, decreased prostatic weights by reducing serum concentrations of testosterone and adrenal androgens in rats

Abstract

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 (ED 50 , 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 (ED 50 , 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.

Synthesis and Pharmacological Evaluation of Novel Arylpiperazine Derivatives as Nonsteroidal Androgen Receptor Antagonists

“…7) Thus compounds that block the action or synthesis of androgens have been proven useful in the treatment of diseases such as prostate cancer, benign prostatic hypertrophy, hirsutism, and acne. [8][9][10][11] AR antagonists, 12,13) including cyproterone acetate (1), 14) flutamide (2), [15][16][17] nilutamide (3), 18) and bicalutamide (4), [19][20][21][22] have been used clinically for the treatment of prostate cancer (Fig. 1).…”

Neural responses to aggressive challenge correlate with behavior in nonbreeding sparrows

“…Osmotic minipumps containing 50% DMSO in DH 2 O (vehicle) or YM116 (C17,20 lyase inhibitor; a kind gift of Dr. Hisataka Shikama, Yamanouchi Pharmaceuticals, Japan) [13,14] were placed subcutaneously in the back (after [9]). YM116 is a potent and specific inhibitor of DHEA synthesis.…”

“…YM116 is a potent and specific inhibitor of DHEA synthesis. Based on rodent studies [14] and our pilot songbird studies, the dose was set at ∼10 mg/kg body weight/day. Silastic implants (7 mm long, 0.76 mm i.d., 1.65 mm o.d.)…”

Determination of 17α-hydroxylase-C17,20-lyase (P45017α) enzyme activities and their inhibition by selected steroidal picolyl and picolinylidene compounds

“…iC 50 parameters of references ketoconazole and abiraterone were found 1.86 ± 0.25 μM and 0.034 ± 0.003 µM for 17α-hydroxylase, and 0.32 ± 0.02 µM and 0.0125 ± 0.0015 µM for C 17,20 -lyase in our P450 17α inhibition test, respectively. these reference results are in good agreement with values found in the literature [4,9,15,18,23,[31][32]34]. Table 1 In vitro inhibition of 17α-hydroxylase and C 17,20 -lyase activities of the rat testicular P450 …”