Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies

Migliore, Marco; Habrant, Damien; Sasso, Oscar; Albani, Clara; Bertozzi, Sine Mandrup; Armirotti, Andrea; Piomelli, Daniele; Scarpelli, Rita

doi:10.1016/j.ejmech.2015.12.036

Cited by 30 publications

(22 citation statements)

References 67 publications

(83 reference statements)

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“…Taken together, the studies above suggest that a compound with dual-action effects towards both cyclooxygenase (COX, the primary target of NSAIDs) and FAAH (or monoacylglycerol lipase) may be a potentially useful anti-inflammatory agent lacking the problematic gastrointestinal unwanted effects associated with NSAIDs. In 2015, the Piomelli group reported the synthesis and pharmacological properties of ARN2508 ((±)À2-[3-fluoro-4-[3-(hexylcarbamoyloxy)phenyl]phenyl]propanoic acid), a compound combining the structural elements of URB597 and the NSAID flurbiprofen 7,8 . The compound inhibited FAAH, COX-1 and COX-2 with IC 50 values of 31, 12 and 420 nM, respectively, and produced anti-inflammatory effects in vivo without causing gastric irritation 7 .…”

Section: Introductionmentioning

confidence: 99%

Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen

Deplano

Karlsson

Svensson

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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2020) Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen, Journal of Enzyme Inhibition and Medicinal Chemistry, 35:1, 815-823, ABSTRACT Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by nonsteroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)À2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [ 3 H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a K i value of 0.26 mM and an a value of 4.9. At a concentration of 10 mM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor. ARTICLE HISTORY

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Section: Introductionmentioning

confidence: 99%

Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen

Deplano

Karlsson

Svensson

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…This compound also showed COX-2 (IC 50 = 0.43 ± 0.002 µ M) inhibitory activity. 58 Naproxen is a classic nonselective COX inhibitor used as an antiinflammatory agent, while tomoxiprole is a selective COX-2 inhibitor. 59 Structural features of naproxen and tomoxiprole were merged to produce a new molecule, 80.…”

Section: Hybrid Molecules Comprising Merged Pharmacophoresmentioning

confidence: 99%

Hybrid organic molecules as antiinflammatory agents; a review of structural features and biological activity

Mohsin¹,

Ahmad²

2018

Turk J Chem

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Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation.Some undesirable effects are linked with NSAIDs such as the gastrointestinal tract (GIT) toxicity and cardiovascular disturbances. At present the preparation of a hybrid molecular technique is being used to produce new analgesic and antiinflammatory molecules. Attachment of NSAIDs with nitric oxide and hydrogen sulfide releasing molecules produced some gastroprotective agents with improved analgesic and antiinflammatory activities. Combination of NSAIDs with different biologically active 5-membered, 6-membered, and condensed heterocyclic rings has also led to the formation of some potent molecules. Some of these hybrid molecules, e.g., ibuprofen-thiazole, exhibited less GIT toxicity, while others showed selectivity for COX-2 enzyme, e.g., quinazolinone-pyrimidine and benzothiophene-rhodanine hybrids. COX-2 selectivity was also exhibited by hybrids of NSAIDs with natural molecules such as salicylates-resveratrol, chromoneoxindole, and chrysin-indole-pyrazole. The preparation of new hybrid molecules is significant because they can serve as a lead compound for the discovery and development of safer analgesic and antiinflammatory agents.

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“…These attempts proved successful, as a number of multitarget FAAH-COX inhibitors were shown to suppress intestinal inflammation and protect against nonsteroidal anti-inflammatory drug-dependent GI damage (e.g., see Refs. 33,34).…”

Section: Endocannabinoid Synthesis and Degradationmentioning

confidence: 99%

Cannabinoids as gastrointestinal anti‐inflammatory drugs

Fabisiak

Fichna

2017

Neurogastroenterology Motil

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In this mini-review, we focus on the potential of the endocannabinoid system as a target for novel therapies to treat gastrointestinal (GI) inflammation. We discuss the organization of the endocannabinoid signaling and present possible pharmacological sites in the endocannabinoid system. We also refer to recent clinical findings in the field. Finally, we point at the potential use of cannabinoids at low, non-psychoactive doses to counteract non-inflammatory pathological events in the GI tract, like chemotherapy-induced diarrhea, as evidenced by Abalo et al. in the rat model.

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Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies

Cited by 30 publications

References 67 publications

Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen

Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen

Hybrid organic molecules as antiinflammatory agents; a review of structural features and biological activity

Cannabinoids as gastrointestinal anti‐inflammatory drugs

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