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.
J Med Chem, 2002/8/01;45(16):3406-17.
Picard F[1], Barassin S, Mokhtarian A, Hartmann RW
Affiliations
PMID: 12139451
Impact factor: 8.039
Abstract
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.
MeSH terms
5-alpha Reductase Inhibitors; Animals; Benzoates; Chromatography, High Pressure Liquid; Enzyme Inhibitors; Humans; Isoenzymes; Male; Models, Molecular; Orchiectomy; Organ Size; Piperidines; Prostate; Rats; Structure-Activity Relationship; Testosterone
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