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

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Feledziak, Marion [UCL] Michaux, Catherine [FUNDP] Urbach, Allan [UCL] Labar, Geoffray [UCL] Muccioli, Giulio [UCL] Lambert, Didier [UCL] Marchand-Brynaert, Jacqueline [UCL]

A library of 30 beta-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 omega-alkenoyl and omega-arylalkanoyl chains. All compounds were selective inhibitors of hFAAH versus hMGL, and IC(50) 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.

Document type Article de périodique (Journal article) – Article de recherche – Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
Access type Accès restreint
Publication date 2009
Language Anglais
Journal information "Journal of Medicinal Chemistry" - Vol. 52, no. 22, p. 7054-7068 (2009)
Peer reviewed yes
Publisher American Chemical Society ((United States) Washington)
issn 0022-2623
e-issn 1520-4804
Publication status Publié
Affiliation UCL - MD/FARM - Ecole de pharmacie
MESH Subject Monoacylglycerol Lipases - antagonists & inhibitors - chemistry - metabolism ; Molecular Conformation ; Models, Molecular ; Inhibitory Concentration 50 ; Humans ; Enzyme Inhibitors - chemical synthesis - chemistry - metabolism - pharmacology ; Carbapenems - chemical synthesis - chemistry - metabolism - pharmacology ; Amidohydrolases - antagonists & inhibitors - chemistry - metabolism
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Bibliographic reference Feledziak, Marion ; Michaux, Catherine ; Urbach, Allan ; Labar, Geoffray ; Muccioli, Giulio ; et. al. Beta-lactams derived from a carbapenem chiron are selective inhibitors of human fatty acid amide hydrolase versus human monoacylglycerol lipase. In: Journal of Medicinal Chemistry, Vol. 52, no. 22, p. 7054-7068 (2009)
Permanent URL http://hdl.handle.net/2078.1/28546