Steroid 5alpha-reductase (5alphaR) inhibitory potency of three N-(dicyclohexyl)acetyl-piperidine-4-(benzylidene-4-carboxylic acids) and their corresponding methyl
esters was monitored for type 2
isoenzyme in a
benign prostatic hyperplasia cell free preparation and for type 1
isoenzyme in DU145 cells and in a cell free assay. The hydrolytic stability of the
esters and their bioconversion to the corresponding
acids was assessed in aqueous buffered
solution (pH 7.4) and in selected biological media having measurable
esterase activities. The
carboxylic acids 1, 2, and 3 with high type 2 inhibitory potencies displayed only little type 1 inhibition. The
esters 1a, 2a, and 3a, originally designed as
prodrugs to enhance cell permeation, proved to be potent type 1 inhibitors and are therefore acting as drugs themselves. They are stable in buffered
salt solution (pH 7.4), Caco-2 cells, and human plasma, whereas all
esters are cleaved into the corresponding
acids in
benign prostatic hyperplasia tissue homogenate. Methyl
esters, applied as hydrolytically stable precursor drugs to facilitate cell permeation, will yield the corresponding
carboxylic acids as type 2 inhibitors after hydrolysis in the target organ. The
esters themselves--stable in human plasma and Caco-2 cells--are acting as potent drugs toward 5alphaR type 1. Thus, dual inhibition of 5alphaR type 1 and type 2 can be achieved by applying a single parent compound.