4-(Benzoylindolizinyl)butyric acids; novel nonsteroidal inhibitors of steroid 5alpha-reductase. III.
A novel series of indolizinebutyric acids with various benzoyl substituents was synthesized to develop nonsteroidal inhibitors of steroid 5alpha-reductase, and the structure-activity relationships in this series were studied. We previously reported the structure-activity relationships in a series of indolebutyric acids as well as the discovery of the novel nonsteroidal 5alpha-reductase inhibitor, FK143. We have now made other modifications to this compound to improve in vivo inhibitory activity. By altering the heterocyclic nucleus and changing the benzoyl substituent we have succeeded in identifying the strongly active compound, FK687, (S)-4-[1-[4-[[1-(4-isobutylphenyl)butyl]oxy]benzoyl]indolizin-3-yl]butyric acid, which displays strong in vitro inhibitory activity against the human enzyme and in vivo inhibitory activity against the castrated young rat model. This compound should be a useful agent for the treatment of benign prostatic hyperplasia.
Sawada
K
K
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Tokodai, Tsukuba, Japan. kouzo_sawada@po.fujisawa.co.jp
Okada
S
S
Kuroda
A
A
Watanabe
S
S
Sawada
Y
Y
Tanaka
H
H
D058891:5-alpha Reductase Inhibitors; D000818:Animals; D002087:Butyrates / Q000138:chemical synthesis* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry; D007212:Indolizines / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009919:Orchiectomy; D011467:Prostate / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar
D058891:5-alpha Reductase Inhibitors; D002087:Butyrates; D004791:Enzyme Inhibitors; D007211:Indoles; D007212:Indolizines