Vol. 290, Issue 3, 1013-1018, September 1999

Z-350, A Novel Compound with ₁-Adrenoceptor Antagonistic and Steroid 5-Reductase Inhibitory Actions: Pharmacological Properties In Vivo

Yoshihisa Fukuta, Youichi Fukuda, Raita Higashino, Kenji Yoshida, Masayuki Ogishima, Hajime Tamaki and Mineo Takei

Central Research Laboratories, Zeria Pharmaceutical Co. Ltd., Saitama, Japan

The ₁-adrenoceptor-antagonistic and steroid 5-reductase-inhibitory actions of Z-350 [(S)-4-{3-{4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy}benzoyl}indole-1-yl}butyric acid hydrochloride] were investigated in rabbits and rats in vivo. Z-350 (1-30 mg/kg), administered intraduodenally, dose-dependently inhibited phenylephrine-induced increases in prostatic urethral pressure with an ED₅₀ value of 3.8 mg/kg in anesthetized male rabbits, whereas the effects on mean blood pressure and orthostatic hypotensive response were weaker when compared with other ₁-adrenoceptor antagonists, tamsulosin and prazosin. Z-350 (1-10 mg/kg p.o.) dose-dependently inhibited the prostatic steroid 5-reductase activity in rats with an ED₅₀ value of 2.8 mg/kg. The daily oral administration of Z-350, at 10 mg/kg for 7 days, significantly reduced the prostatic growth induced by testosterone in castrated rats, with no effect on dihydrotestosterone-induced prostatic growth. These results indicate that Z-350 exhibited ₁-adrenoceptor-antagonistic and 5-reductase inhibitory actions at almost equal doses in vivo, and was expected to improve the bladder outlet obstruction associated with benign prostatic hyperplasia with smaller cardiovascular adverse effect.