Vinyl fluoride as a mimic of the "intermediate' enol form in the 5 alpha-reductase transformation: synthesis and in vitro activity of (N-1',1'-dimethylethyl)-3-haloandrost-3,5-diene-17 beta-carboxamides.
(N-1',1'-Dimethylethyl)-3-haloandrost-3,5-diene-17 beta-carboxamides (9-11) and the methyl ester 8 were prepared from 3-chloro/bromoandrost-3,5-diene-17 beta-carboxylic chloride/bromide (6/7), which were obtained from pregnenolone. In comparison with finasteride and 4-MA, compounds 8-11 showed very weak inhibitory activity ( < or = 10% inhibition) on human type I 5 alpha-reductase (transfected 293 cells) at 100 and 1000 nM concentrations. Against the type II enzyme, chloro compounds 8 and 9, and bromo 10 had no effect at 100 nM concentration, however, they were weak inhibitors of the type II (6.0% < inhibition < 30%) at a higher concentration. The best activity (IC50 = 480 nM) was observed with the 3-vinyl fluoride analogue 11.
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Medicinal Chemistry Division, Laboratory of Molecular Endocrinology, C.H.U.L. Research Center, Québec City, Canada.
Singh
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Luu-The
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Côté
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Laplante
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Labrie
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D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors; D000730:Androstadienes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000736:Androstenes / Q000737:chemistry; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018120:Finasteride; D006219:Halogens / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes; D013329:Structure-Activity Relationship; D014162:Transfection; D014753:Vinyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D058891:5-alpha Reductase Inhibitors; D000730:Androstadienes; D000736:Androstenes; D004791:Enzyme Inhibitors; D006219:Halogens; D007527:Isoenzymes; C100553:N-(1',1'-dimethylethyl)-3-fluoroandrost-3,5-dien-17-carboxamide; D014753:Vinyl Compounds; C016829:vinyl fluoride; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase