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 agentsShow others and affiliations
2021 (English)In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 36, no 1, p. 940-953Article in journal (Refereed) Published
Abstract [en]
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.
Place, publisher, year, edition, pages
Taylor & Francis, 2021. Vol. 36, no 1, p. 940-953
Keywords [en]
allodynia, cyclooxygenase, endocannabinoid, FAAH inhibition, fatty acid amide hydrolase, Flurbiprofen amides, hyperalgesia, non-steroidal anti-inflammatory drugs
National Category
Pharmacology and Toxicology Medicinal Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-183361DOI: 10.1080/14756366.2021.1875459ISI: 000643799500001PubMedID: 33896320Scopus ID: 2-s2.0-85105117861OAI: oai:DiVA.org:umu-183361DiVA, id: diva2:1557172
2021-05-252021-05-252023-09-05Bibliographically approved