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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
Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, Department of Life and Environmental Sciences, University of Cagliari, Monserrato, Italy.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).ORCID iD: 0000-0001-8572-5841
Department of Pharmacy, University of Naples Federico II, Naples, Italy; Net4Science srl, University “Magna Graecia”, Catanzaro, Italy.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
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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
Available from: 2021-05-25 Created: 2021-05-25 Last updated: 2023-09-05Bibliographically approved

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Karlsson, JessicaSvensson, MonaFowler, Christopher J.

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