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 5alpha-reductase-inhibitory actions of Z-350 [(S)-4-{3-{4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-y l]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(50) 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-dependently inhibited the prostatic steroid 5alpha-reductase activity in rats with an ED(50) 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 alpha(1)-adrenoceptor-antagonistic and 5alpha-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.
Fukuta
Y
Y
Central Research Laboratories, Zeria Pharmaceutical Co. Ltd., Saitama, Japan.
Fukuda
Y
Y
Higashino
R
R
Yoshida
K
K
Ogishima
M
M
Tamaki
H
H
Takei
M
M
D058891:5-alpha Reductase Inhibitors; D000284:Administration, Oral; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004386:Duodenum; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology; D007024:Hypotension, Orthostatic / Q000188:drug therapy; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology*; D011467:Prostate / Q000033:anatomy & histology / Q000201:enzymology; D011470:Prostatic Hyperplasia / Q000188:drug therapy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D013739:Testosterone / Q000494:pharmacology; D014521:Urethra / Q000187:drug effects / Q000502:physiology
D058891:5-alpha Reductase Inhibitors; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D004791:Enzyme Inhibitors; D006133:Growth Substances; D007211:Indoles; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; C121225:Z 350; D013196:Dihydrotestosterone; D010656:Phenylephrine; D013739:Testosterone