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. (1st January 2021)

• Record Type: Journal Article
• Authors: Deplano, Alessandro; Karlsson, Jessica; Moraca, Federica; Svensson, Mona; Cristiano, Claudia; Morgillo, Carmine Marco; Fowler, Christopher J.; Russo, Roberto; Catalanotti, Bruno; Onnis, Valentina
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 36:Number 1(2021)
• Page Start: 940
• Page End: 953
• Publication Date: 2021-01-01
• Subjects: Flurbiprofen amides -- FAAH inhibition -- fatty acid amide hydrolase -- endocannabinoid -- cyclooxygenase -- non-steroidal anti-inflammatory drugs -- hyperalgesia -- allodynia; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2021.1875459
• Languages: English
• ISSNs: 1475-6366

Abstract

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. Graphical Abstract: