Nitric oxide releasing derivatives of tolfenamic acid with anti-inflammatory activity and safe gastrointestinal profile

Ziakas, G.; Rekka, Eleni A.; Gavalas, Antonis; Eleftheriou, Phaedra; Tsiakitzis, Karyofyllis; Kourounakis, Panos N.

doi:10.1016/j.bmc.2005.07.049

Cited by 25 publications

(18 citation statements)

References 52 publications

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“…The anti‐inflammatory efficacy of several NO‐donating derivatives of diclofenac, flurbiprofen, ketoprofen, naproxen, mesalamine, aspirin, indomethacin, ibuprofen, tolfenamic acid, and celecoxib has been reported using various animal models of acute and chronic inflammation. For instance, naproxcinod (Table ) and P2026 (an NO‐releasing derivative of diclofenac) have shown potent anti‐inflammatory activity either in a carrageenan‐induced paw edema model or in an adjuvant‐induced arthritis model .…”

Section: Association Of Nsaids With Protective Mediatorsmentioning

confidence: 99%

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Pereira-Leite

Nunes

Jamal

et al. 2016

Medicinal Research Reviews

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The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy.

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Section: Association Of Nsaids With Protective Mediatorsmentioning

confidence: 99%

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Pereira-Leite

Nunes

Jamal

et al. 2016

Medicinal Research Reviews

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“…Tolfenamic acid is a fenamic acid derivative indicated for use in migraine. Intending to improve anti‐inflammatory activity and GI tolerability of tolfenamic acid, Ziakas and co‐workers developed NO‐releasing analogs of tolfenamic acid . Among them, 3‐nitrooxypropyl 2‐(3‐chloro‐2‐methylphenyl amino)benzoate ( 21 ) exhibited highest activity against COX‐2, while compound 2‐nitrooxy‐1‐nitrooxymethylethyl 2‐(3‐chloro‐2‐methylphenylamino)benzoate ( 22 ) was found to be a better inhibitor of LOX.…”

Section: Development Of Various Nsaids and Their Derivativesmentioning

confidence: 99%

Recent Developments in Chimeric NSAIDs as Safer Anti‐Inflammatory Agents

Kumar

Sharma

2014

Medicinal Research Reviews

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NSAIDs are among the most widely prescribed medications across the world, but the gastrointestinal (GI) toxicity still remains the biggest problem and the challenge for current NSAIDs-based therapeutics. The development of selective COX-2 inhibitors was driven by the assumption that selective inhibition of COX-2 would reduce the GI side effects. However, the initial enthusiasm for selective COX-2 inhibitors has faded away due to the emergence of serious side effects associated with the long-term use of these NSAIDs. In the recent years, a number of novel approaches to develop gastrosparing NSAIDs have been explored with the promising results. This review deals with such approaches and strategies that have been employed in the last two decades and are being used currently in the design and development of safer NSAIDs.

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“…Compound 43 was prepared from 4 and 4-nitrooxy-butan-1-ol 90 using the same procedure described for 42 . Product was purified by column chromatography (SiO 2 , hexane/ethyl acetate 2:1, 65%).…”

Section: Methodsmentioning

confidence: 99%

Design and Synthesis of Neuroprotective Methylthiazoles and Modification as NO-Chimeras for Neurodegenerative Therapy

et al. 2012

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Learning and memory deficits in Alzheimer’s disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described, which uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (MZ) derivatives were synthesized, based upon a lead neuroprotective pharmacophore acting in part by GABAA receptor potentiation. MZ derivatives were assayed for protection of primary neurons against oxygen-glucose deprivation and excitotoxicity. Selected neuroprotective derivatives were incorporated into NO-chimera prodrugs, coined nomethiazoles. To provide proof of concept for the nomethiazole drug class, selected examples were assayed for: restoration of synaptic function in hippocampal slices from AD-transgenic mice; reversal of cognitive deficits; and, brain bioavailability of the prodrug and its neuroprotective MZ metabolite. Taken together the assay data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD.

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Nitric oxide releasing derivatives of tolfenamic acid with anti-inflammatory activity and safe gastrointestinal profile

Cited by 25 publications

References 52 publications

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Recent Developments in Chimeric NSAIDs as Safer Anti‐Inflammatory Agents

Design and Synthesis of Neuroprotective Methylthiazoles and Modification as NO-Chimeras for Neurodegenerative Therapy

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