Vinyl fluoride as a mimic of the ‘intermediate’ enol form in the 5α-reductase transformation: Synthesis and in vitro activity of ( N-1′,1′-Dimethylethyl)-3-haloandrost-3,5-diene-17 β-carboxamides

Abstract

( N-1′,1′-Dimethylethyl)-3-haloandrost-3,5-diene-17 β-carboxamides (9–11) and the methyl ester 8 were prepared from 3-chloro/bromoandrost-3,5-diene-17β-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 (≤10% inhibition) on human type I 5α-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 (IC 50 = 480 nM) was observed with the 3-vinyl fluoride analogue 11.