Synthesis of tricyclic compounds as steroid 5alpha-reductase inhibitors.
A series of 4-phenoxybutyric acid derivatives attached to a tricyclic skeleton were prepared and evaluated as 5alpha-reductase inhibitors. Structure activity relationships for these compounds in terms of rat epididymis (type 2) 5alpha-reductase inhibitory activities reveal that 1) the substitution pattern at the 11-position of dibenz[b,e]oxepin influenced potency, 2) higher lipophilicity of the tricyclic skeleton improved potency, whereas the existence of a basic nitrogen atom in this skeleton was detrimental to potency, and 3) isobutyl substitution at the 8 positon of the azepine skeleton was tolerated. Among the tricyclic compounds studied, 4-[3-[5-benzyl-8-(2-methyl)propyl-10,11-dihydrodibenz[b,f]azepine- 2-carboxamido]phenoxy]butyric acid (26) was the most potent inhibitor of rat type 2 5alpha-reductase at 0.1 microM.
Takami
H
H
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Nagaizumi, Shizuoka, Japan.
Nonaka
H
H
Kishibayashi
N
N
Ishii
A
A
Kase
H
H
Kumazawa
T
T
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D002087:Butyrates / Q000737:chemistry* / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003990:Dibenzoxepins / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004822:Epididymis / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008956:Models, Chemical; D051381:Rats; D013329:Structure-Activity Relationship
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D001381:Azepines; D001549:Benzamides; D002087:Butyrates; D002227:Carbazoles; D003990:Dibenzoxepins; D004791:Enzyme Inhibitors; C076552:ONO 3805; C041514:carbazole