A comparison of the cyclooxygenase inhibitor-NO donors (CINOD), NMI-1182 and AZD3582, using in vitro biochemical and pharmacological methods

Young, Delano V.; Cochran, Edward; Dhawan, Vijay; Earl, Richard A.; Ellis, James L.; Garvey, David S.; Janero, David R.; Khanapure, Subhash P.; Letts, L. Gordon; Melim, Terry; Murty, Madhavi G.; Shumway, Matthew J.; Wey, Shiow‐Jyi; Zemtseva, Irina S.; Selig, William M.

doi:10.1016/j.bcp.2005.08.004

Cited by 10 publications

(3 citation statements)

References 28 publications

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“…NO‐NSAIDs consist in a parent NSAID covalently linked to a spacer that, in turn, is associated with a NO‐releasing moiety. In the last two decades, several NO‐NSAIDs have been synthesized using different spacers and NO‐donating moieties (Table ) . Most NO‐NSAIDs have an ester linkage but some were designed with a disulfide linker .…”

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 Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity.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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“…Given the tolerance issues associated with organic nitrates, it is surprising that the majority of nitroaspirins investigated so far exploit the same NO donor moiety, especially as it has been shown for at least one example that the mechanism of NO release is the same in hybrid drugs ( Turnbull et al ., 2006a ). This is a pressing concern considering the rapid emergence of many new NSAIDs/anti‐inflammatory/analgesic agents with nitrates groups, for example paracetamol ( Marshall et al ., 2006 ), flurbiprofen ( Fujihara et al ., 1998 ), naproxen ( Young et al ., 2005 ), mesalamine ( Wallace et al ., 1999b ), gabapentin ( Wu et al ., 2004 ), predisolone and other steroids ( Tallet et al ., 2002 ). However, the nitrate ester of nitroaspirin has been replaced with a furoxan moiety ( Cena et al ., 2003 ; Turnbull et al ., 2006a ) and S ‐nitroso‐ ( Bandarage et al ., 2000 ) and diazeniumdiolate ( Velazquez et al ., 2005 ) forms of other NSAID drugs (e.g.…”

Section: No Hybrid Drugsmentioning

confidence: 99%

Recent developments in nitric oxide donor drugs

Miller

Megson²

2007

British J Pharmacology

551

432

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During the 1980s, the free radical, nitric oxide (NO), was discovered to be a crucial signalling molecule, with wide-ranging functions in the cardiovascular, nervous and immune systems. Aside from providing a credible explanation for the actions of organic nitrates and sodium nitroprusside that have long been used in the treatment of angina and hypertensive crises respectively, the discovery generated great hopes for new NO-based treatments for a wide variety of ailments. Decades later, however, we are still awaiting novel licensed agents in this arena, despite an enormous research effort to this end. This review explores some of the most promising recent advances in NO donor drug development and addresses the challenges associated with NO as a therapeutic agent.

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“…At the same time, it must also release and deliver substantial proportion of NO to the stomach, for its gastro-protective action, the primary site of the ulceration and bleeding caused by 'unwanted' COX inhibition (Young et al 2005). The cleavage pattern of molecule is governed by chemical nature of the 'linker' that connects NSAID to the NOreleasing moiety.…”

Section: Discussionmentioning

confidence: 99%

Oral bioavailability, efficacy and gastric tolerability of P2026, a novel nitric oxide-releasing diclofenac in rat

Pathan

Pamidiboina²,

Deshattiwar

et al. 2010

Inflammopharmacol

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The present study was designed to evaluate, P2026 [(2-((2-(nitrooxy)ethyl)disulfanyl)ethyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate)], a novel NO (nitric oxide) donor prodrug of diclofenac for its ability to release NO and diclofenac, and whether P2026 provides advantage of improved activity/gastric tolerability over diclofenac. Oral bioavailability of P2026 was estimated from plasma concentration of diclofenac and nitrate/nitrite (NOx). Anti-inflammatory activity was evaluated in three different models of inflammation: acute (carrageenan-induced paw oedema), chronic (adjuvant-induced arthritis), and systemic (lipopolysaccharide-induced endotoxic shock). Gastric tolerability was evaluated from compound's propensity to cause gastric ulcers. P2026 exhibited dose-dependent diclofenac and NOx release. Similar to diclofenac, P2026 showed potent anti-inflammatory activity in acute and chronic model, whereas it improved activity in systemic model. Both diclofenac and P2026 inhibited gastric prostaglandin, but only diclofenac produced dose-dependent haemorrhagic ulcers. Thus, the results suggest that coupling of NO and diclofenac contribute to improved gastric tolerability while retaining the anti-inflammatory properties of diclofenac.

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A comparison of the cyclooxygenase inhibitor-NO donors (CINOD), NMI-1182 and AZD3582, using in vitro biochemical and pharmacological methods

Cited by 10 publications

References 28 publications

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Recent developments in nitric oxide donor drugs

Oral bioavailability, efficacy and gastric tolerability of P2026, a novel nitric oxide-releasing diclofenac in rat

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