Document Detail

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.
MedLine Citation:
PMID:  15627259     Owner:  NLM     Status:  MEDLINE    
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.
Martina Streiber; Franck Picard; Christiane Scherer; Stefanie B Seidel; Rolf W Hartmann
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  94     ISSN:  0022-3549     ISO Abbreviation:  J Pharm Sci     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-02-07     Completed Date:  2005-07-21     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  473-80     Citation Subset:  IM    
Copyright Information:
Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association.
Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, D-66041 Saarbruecken, Germany.
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MeSH Terms
Benzylidene Compounds / chemistry,  pharmacology*
Caco-2 Cells
Carboxylic Acids / chemistry,  pharmacology*
Cell Line, Tumor
Enzyme Inhibitors / chemistry,  pharmacology*
Isoenzymes / antagonists & inhibitors,  classification,  metabolism
Piperidines / chemistry,  pharmacology*
Prodrugs / chemistry,  pharmacology*
Testosterone 5-alpha-Reductase / antagonists & inhibitors*,  classification,  metabolism
Reg. No./Substance:
0/Benzylidene Compounds; 0/Carboxylic Acids; 0/Enzyme Inhibitors; 0/Esters; 0/Isoenzymes; 0/Piperidines; 0/Prodrugs; EC 5-alpha-Reductase

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