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.
Ideyama
Y
Y
Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
Kudoh
M
M
Tanimoto
K
K
Susaki
Y
Y
Nanya
T
T
Nakahara
T
T
Ishikawa
H
H
Yoden
T
T
Okada
M
M
Fujikura
T
T
Akaza
H
H
Shikama
H
H
D000069501:Abiraterone Acetate; D000311:Adrenal Glands / Q000502:physiology; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000728:Androgens / Q000096:biosynthesis / Q000097:blood*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D009919:Orchiectomy; D009929:Organ Size; D011467:Prostate / Q000033:anatomy & histology*; D051381:Rats; D012669:Seminal Vesicles / Q000033:anatomy & histology; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis / Q000097:blood*
D000728:Androgens; D000730:Androstadienes; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; C114168:YM 116; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D000324:Adrenocorticotropic Hormone; D013254:Steroid 17-alpha-Hydroxylase; D000069501:Abiraterone Acetate; C061121:liarozole; D007654:Ketoconazole