Design, synthesis and in vitro and in vivo biological evaluation of flurbiprofen amides as new fatty acid amide hydrolase/cyclooxygenase-2 dual inhibitory potential analgesic agents

J Enzyme Inhib Med Chem. 2021 Dec;36(1):940-953. doi: 10.1080/14756366.2021.1875459.

Abstract

Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds.

Keywords: FAAH inhibition; Flurbiprofen amides; allodynia; cyclooxygenase; endocannabinoid; fatty acid amide hydrolase; hyperalgesia; non-steroidal anti-inflammatory drugs.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Analgesics / chemical synthesis
  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Animals
  • Cyclooxygenase 2 / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Flurbiprofen / chemical synthesis
  • Flurbiprofen / chemistry
  • Flurbiprofen / pharmacology*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Models, Molecular
  • Molecular Structure
  • Quantum Theory
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Static Electricity
  • Structure-Activity Relationship

Substances

  • Amides
  • Analgesics
  • Enzyme Inhibitors
  • Flurbiprofen
  • Cyclooxygenase 2
  • Amidohydrolases
  • fatty-acid amide hydrolase

Grants and funding

VO would like to thank the University of Cagliari (grant FIR 2018–19). FM was supported by a fellowship of Regione Campania (n. B61C17000070007 – SATIN). BC gratefully acknowledges the support of NVIDIA Corporation with the donation of the Titan Xp GPU used for this research, and the SCoPE datacenter of the University Federico II for the access to HPC infrastructures.