Methyl esters of N-(dicyclohexyl)acetyl-piperidine-4-(benzylidene-4-carboxylic acids) as drugs and prodrugs: a new strategy for dual inhibition of 5 alpha-reductase type 1 and type 2.
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.
Streiber
Martina
M
Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, D-66041 Saarbruecken, Germany.
Picard
Franck
F
Scherer
Christiane
C
Seidel
Stefanie B
SB
Hartmann
Rolf W
RW
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000145:classification / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000145:classification / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*
D058891:5-alpha Reductase Inhibitors; D001597:Benzylidene Compounds; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D004952:Esters; D007527:Isoenzymes; D010880:Piperidines; D011355:Prodrugs; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase