(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

Caruano, Joséphine;Feledziak, Marion;Labar, Geoffray;Michaux, Catherine;Marchand-Brynaert, Jacqueline;et.al.
(2014) Journal of Enzyme Inhibition and Medicinal Chemistry — Vol. 29, p. 654-662 (2014)

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Authors
  • Caruano, JoséphineUCLouvain
    Author
  • Feledziak, MarionUCLouvain
    Author
  • Labar, GeoffrayUCLouvain
    Author
  • Michaux, CatherineFUCaM
    Author
  • Muccioli, Giulioorcid-logoUCLouvain
    Author
  • Robiette, Raphaëlorcid-logoUCLouvain
    Author
  • Marchand-Brynaert, JacquelineUCLouvain
    Author
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Abstract
A series of lipophilic ester derivatives (2a-g) of (S)-1-(pent-4’-enoyl)-4-(hydroxymethyl)-azetidin-2-one has been synthesized in three steps from (S)-4-(benzyloxycarbonyl)-azetidin-2-one and evaluated as novel, reversible, ?-lactamic inhibitors of endocannabinoid-degrading enzymes (hFAAH and hMAGL). The compounds showed IC50 values in the micromolar range and selectivity for hFAAH versus hMAGL. The unexpected thousandfold decrease of activity of 2a comparatively to the known regioisomeric structure 1a (i.e. lipophilic chains placed on N1 and C3 positions of the ?-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.
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Caruano, J., Feledziak, M., Labar, G., Michaux, C., Perpete, E., Muccioli, G., Robiette, R., & Marchand-Brynaert, J. (2014). (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. Journal of Enzyme Inhibition and Medicinal Chemistry, 29, 654-662. https://doi.org/10.3109/14756366.2013.837900 (Original work published 2014)