Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide. (February 2013)

• Record Type: Journal Article
• Authors: Fowler, Christopher J.; Björklund, Emmelie; Lichtman, Aron H.; Naidu, Pattipati S.; Congiu, Cenzo; Onnis, Valentina
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 28:Number 1(2013:Feb.)
• Page Start: 172
• Page End: 182
• Publication Date: 2013-02
• Subjects: Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.3109/14756366.2011.643304
• Languages: English
• ISSNs: 1475-6366

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <p>A dual-action cyclooxygenase (COX)–fatty acid amide hydrolase (FAAH) inhibitor may have therapeutic usefulness as an analgesic, but a key issue is finding the right balance of inhibitory effects. This can be done by the design of compounds exhibiting different FAAH/COX-inhibitory potencies. In the present study, eight ibuprofen analogues were investigated. Ibuprofen (<bold>1</bold>), 2-(4-Isobutylphenyl)-<italic>N</italic>-(2-(3-methylpyridin-2-ylamino)-2-oxoethyl)propanamide (<bold>9</bold>) and <italic>N</italic>-(3-methylpyridin-2-yl)-2-(4′-isobutylphenyl)propionamide (<bold>2</bold>) inhibited FAAH with IC₅₀ values of 134, 3.6 and 0.52 µM respectively. The corresponding values for COX-1 were ~29, ~50 and ~60 µM, respectively. Using arachidonic acid as substrate, the compounds were weak inhibitors of COX-2. However, when anandamide was used as COX-2 substrate, potency increased, with approximate IC₅₀ values of ~6, ~10 and ~19 µM, respectively. Compound 2 was confirmed to be active <italic>in vivo</italic> in a murine model of visceral nociception, but the effects of the compound were not blocked by CB receptor antagonists.</p> </abstract>