An unprecedented reversible mode of action of β-lactams for the inhibition of human fatty acid amide hydrolase (hFAAH)

Marion Feledziak, Catherine Michaux, Didier M Lambert, Jacqueline Marchand-Brynaert

Research output: Contribution to journalArticlepeer-review

Abstract

A series of compound was prepared to clarify the reversible mechanism of β-lactamic hFAAH inhibitors on the one hand, and to modulate some of their physicochemical parameters on the other hand. In particular, two compounds (4b and 4e) were designed to display a potential good leaving group on the crucial carbonyl with a view to possibly acylating the active serine of the hFAAH catalytic triad. Reversibility studies showed that these two compounds retain the reversible mode of inhibition, suggesting a noncovalent interaction between our β-lactams and hFAAH. Finally, pharmacological evaluations of bioisosteres of the lead compound (4a, IC(50) = 5.3 nM) revealed that log P values and PSA could be optimized without altering the FAAH inhibition (IC(50) values from 3.65 nM to 70.9 nM).

Original languageEnglish
Pages (from-to)101-11
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume60
DOIs
Publication statusPublished - 2013

Keywords

  • Amidohydrolases
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • beta-Lactams

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