β-Lactams Derived from a Carbapenem Chiron Are Selective Inhibitors of Human Fatty Acid Amide Hydrolase versus Human Monoacylglycerol Lipase

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• 作者：Marion Feledziak ; Catherine Michaux ; Allan Urbach ; Geoffray Labar ; Giulio G. Muccioli ; Didier M. Lambert ; Jacqueline Marchand-Brynaert
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：November 26, 2009
• 年：2009
• 卷：52
• 期：22
• 页码：7054-7068
• 全文大小：1121K
• 年卷期：v.52,no.22(November 26, 2009)
• ISSN：1520-4804

文摘

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.