Synthesis and evaluation of 2'-substituted 4-(4'-carboxy- or 4'-carboxymethylbenzylidene)-N-acylpiperidines: highly potent and in vivo active steroid 5alpha-reductase type 2 inhibitors.
Sixteen compounds derived from N-acyl-4-benzylidenepiperidine-4'-carboxylic acids were synthesized and evaluated for inhibition of rat and human steroid 5alpha-reductase isozymes types 1 and 2. In the dicyclohexylacetyl series, fluorination in the 2-position of the benzene nucleus (15), exchange of the carboxy group by a carboxymethyl moiety (20), and combination of both structural modifications (25) led to highly active inhibitors of the human type 2 isozyme (IC(50) values: 15, 11 nM; 20, 6 nM; 25, 7 nM; finasteride, 5 nM). In vivo all compounds tested markedly reduced the prostate weights in castrated testosterone-treated rats. Oral activity was shown for compound 7. From the finding that compound 15 is active in the rat, although it is a rather poor inhibitor of the rat enzyme and is a strong inhibitor of the human enzyme, it is concluded that it should be highly potent in men.
Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 15 11 50, D-66041 Saarbrücken, Germany.
Franck
F
Picard
Stephan
S
Barassin
Armand
A
Mokhtarian
Rolf W
RW
Hartmann
D058891:5-alpha Reductase Inhibitors; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008958:Models, Molecular; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000494:pharmacology
D058891:5-alpha Reductase Inhibitors; D001565:Benzoates; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C463492:N-(dicyclohexyl)acetylpiperidine-4-(2-fluorobenzylidene-4-carboxylic acid); D010880:Piperidines; D013739:Testosterone