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

Alessandro Deplano, Jessica Karlsson, Federica Moraca, Mona Svensson, Claudia Cristiano, Carmine Marco Morgillo, Christopher J. Fowler, Roberto Russo (Lead / Corresponding author), Bruno Catalanotti (Lead / Corresponding author), Valentina Onnis

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)940-953
Number of pages14
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume36
Issue number1
Early online date26 Apr 2021
DOIs
Publication statusPublished - 2021

Keywords

  • Flurbiprofen amides
  • FAAH inhibition
  • fatty acid amide hydrolase
  • endocannabinoid
  • cyclooxygenase
  • non-steroidal anti-inflammatory drugs
  • hyperalgesia
  • allodynia

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