(S)-1-(Pent-4′-enoyl)-4-(hydroxymethyl)-azetidin-2-one derivatives as inhibitors of human fatty acid amide hydrolase (hFAAH): synthesis, biological evaluation and molecular modelling. (October 2014)

• Record Type: Journal Article
• Authors: Caruano, Joséphine; Feledziak, Marion; Labar, Geoffray; Michaux, Catherine; Perpète, Eric A.; Muccioli, Giulio G.; Robiette, Raphaël; Marchand-Brynaert, Jacqueline
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 29:Number 5(2014:Oct.)
• Page Start: 654
• Page End: 662
• Publication Date: 2014-10
• Subjects: Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.3109/14756366.2013.837900
• Languages: English
• ISSNs: 1475-6366

Abstract

<abstract> <title>Abstract</title> <p>A series of lipophilic ester derivatives (<bold>2a</bold>–<bold>g</bold>) of (<italic>S</italic>)-1-(pent-4<bold>′</bold>-enoyl)-4-(hydroxymethyl)-azetidin-2-one has been synthesised in three steps from (<italic>S</italic>)-4-(benzyloxycarbonyl)-azetidin-2-one and evaluated as novel, reversible, β-lactamic inhibitors of endocannabinoid-degrading enzymes (human fatty acid amide hydrolase (<italic>h</italic>FAAH) and monoacylglycerol lipase (<italic>h</italic>MAGL)). The compounds showed IC₅₀ values in the micromolar range and selectivity for <italic>h</italic>FAAH versus <italic>h</italic>MAGL. The unexpected 1000-fold decrease in activity of <bold>2a</bold> comparatively to the known regioisomeric structure <bold>1a</bold> (i.e. lipophilic chains placed on N₁ and C₃ positions of the β-lactam core) could be explained on the basis of docking studies into a revisited model of <italic>h</italic>FAAH active site, considering one or two water molecules in interaction with the catalytic triad.</p> </abstract>