β-lactams derived from a carbapenem chiron are selective inhibitors of human fatty acid amide hydrolase versus human monoacylglycerol lipase

Marion Feledziak, Catherine Michaux, Allan Urbach, Geoffray Labar, Giulio G. Muccioli, Didier M. Lambert, Jacqueline Marchand-Brynaert

Research output: Contribution to journalArticle

Abstract

A library of 30 β-lactams has been prepared from (3R,4R)-3-[(R)- 1′-(tbutyldimethylsilyloxy)-ethyl]-4-acetoxy-2-azetidinone, and the corresponding deacetoxy derivative, by sequential N- and O-functionalizations with various ω-alkenoyl and ω-arylalkanoyl chains. All compounds were selective inhibitors of hFAAH versus hMGL, and IC50 values in the nanomolar range (5-14 nM) were recorded for the best representatives. From time-dependent preincubation and rapid dilution studies, and from docking analyses in a homology model of the target enzyme, a reversible mechanism of inhibition of hFAAH is proposed.

Original languageEnglish
Pages (from-to)7054-7068
Number of pages15
JournalJournal of Medicinal Chemistry
Volume52
Issue number22
DOIs
Publication statusPublished - 26 Nov 2009

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