(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

Joséphine Caruano, Marion Feledziak, Geoffray Labar, Catherine Michaux, Eric A. Perpète, Giulio G. Muccioli, Raphaël Robiette, Jacqueline Marchand-Brynaert

Research output: Contribution to journalArticlepeer-review

Abstract

A series of lipophilic ester derivatives (2a-g) of (S)-1-(pent-4′-enoyl)-4-(hydroxymethyl)-azetidin-2-one has been synthesised in three steps from (S)-4-(benzyloxycarbonyl)-azetidin-2-one and evaluated as novel, reversible, β-lactamic inhibitors of endocannabinoid-degrading enzymes (human fatty acid amide hydrolase (hFAAH) and monoacylglycerol lipase (hMAGL)). The compounds showed IC50 values in the micromolar range and selectivity for hFAAH versus hMAGL. The unexpected 1000-fold decrease in activity of 2a comparatively to the known regioisomeric structure 1a (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 hFAAH active site, considering one or two water molecules in interaction with the catalytic triad.

Original languageEnglish
Pages (from-to)654-662
Number of pages9
JournalJournal of enzyme inhibition and medicinal chemistry
Volume29
Issue number5
Early online date9 Oct 2013
DOIs
Publication statusPublished - 1 Oct 2014

Keywords

  • Docking
  • Fatty acid amide hydrolase
  • Rapid dilution
  • Reversible inhibition
  • β-lactam

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