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

Abstract

(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.