Z-350, a novel compound with alpha 1-adrenoceptor antagonistic and steroid 5 alpha-reductase inhibitory actions: pharmacological properties in vivo.

The alpha(1)-adrenoceptor-antagonistic and steroid 5 alpha-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 ED,, 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 alpha(1)-adrenoceptor antagonists, tamsulosin and prazosin. Z-350 (1-10 mg/kg p.o.) dose-dependantly inhibited the prostatic steroid 5 alpha-reductase activity in rats with an ED50 value of 2.8 mg/kg. The daily oral administration of Z-350, at greater than or equal to 10 mg/kg for 7 days, significantly reduced the prostatic growth induced by testosterone in castrated rats, with no effect on dihydrotestoterone-induced prostatic growth. These results indicate that Z-350 exhibited alpha(1)-adrenoceptor-antagonistic and 5 alpha-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.