Benzylamides and piperazinoarylamides of ibuprofen as fatty acid amide hydrolase inhibitors

J Enzyme Inhib Med Chem. 2019 Dec;34(1):562-576. doi: 10.1080/14756366.2018.1532418.

Abstract

Fatty Acid Amide Hydrolase (FAAH) is a serine hydrolase that plays a key role in controlling endogenous levels of endocannabinoids. FAAH inhibition is considered a powerful approach to enhance the endocannabinoid signalling, and therefore it has been largely studied as a potential target for the treatment of neurological disorders such as anxiety or depression, or of inflammatory processes. We present two novel series of amide derivatives of ibuprofen designed as analogues of our reference FAAH inhibitor Ibu-AM5 to further explore its structure-activity relationships. In the new amides, the 2-methylpyridine moiety of Ibu-AM5 was substituted by benzylamino and piperazinoaryl moieties. The obtained benzylamides and piperazinoarylamides showed FAAH inhibition ranging from the low to high micromolar potency. The binding of the new amides in the active site of FAAH, estimated using the induced fit protocol, indicated arylpiperazinoamides binding the ACB channel and the cytosolic port, and benzylamides binding the ACB channel.

Keywords: FAAH inhibition; Ibuprofen amides; endocannabinoids; fatty acid amide hydrolase; induced fit docking.

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology*
  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Ibuprofen / chemical synthesis
  • Ibuprofen / chemistry
  • Ibuprofen / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Piperazine / chemistry
  • Piperazine / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amides
  • Enzyme Inhibitors
  • Piperazine
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • Ibuprofen

Grants and funding

This work was supported by the Regione Autonoma della Sardegna Project L.R. 7/2007 under grant no. 2012_CRP-59473 to VO; the University of Cagliari [grant FIR 2016–17] to VO and by the Swedish Research Council under the grant no. 12158, medicine, and the Research Funds of Umeå University Medical Faculty to CJF.