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COX-inhibiting nitric oxide donators (CINODs), also known as NO-NSAIDs, are a new class of non-steroidal anti-inflammatory drug (NSAID) developed with the intention of providing greater safety than existing NSAIDs. These compounds were first described by John Wallace [1] and colleagues. CINODs are hybrid compounds generated by the fusion of an existing NSAID with a nitric oxide (NO)-donating moiety by chemical means, usually by ester linkage. CINODs retain the anti-inflammatory efficacy of NSAIDs via inhibition of cyclooxygenase (COX) while arguably improving upon gastric and vascular safety, most likely via vasorelaxation, inhibition of leukocyte adhesion and reduction of apoptosis, all known effects of NO.

The first CINODs were developed in the 1990s, and as yet none have been approved for use by the general public. The importance of developing such drugs was increased when COX-2-specific NSAIDs rofecoxib (Vioxx) and lumiracoxib (Prexige) were removed from major pharmaceutical markets in the mid-2000s due to vascular safety concerns. Several CINODs are currently being tested in clinical trials, the most advanced of which are being conducted by the French pharmaceutical company NicOx, whose flagship compound naproxcinod is in phase III trials for the treatment of osteoarthritis.[2] Naproxcinod, also known as HCT 3012, AZD3582, NO-naproxen and nitronaproxen, is a fusion of naproxen and a NO-donating group. Other CINODs are also being tested by NicOx for the treatment of diseases in which inflammation plays a role.[3]

References

Wallace JL, Reuter BK, Cicala C, McKnight W, Grisham MB, Cirino G. Novel nonsteroidal anti-inflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology 1994; 107: 172-179. PMID: 8020659
Wallace JL, Cirino G. The development of gastrointestinal-sparing anti-inflammatory drugs. Trends Pharmacol Sci 1994; 15: 405-406. PMID: 7855901
Keeble JE, Moore PK. Pharmacology and potential therapeutic applications of nitric oxide-releasing non-steroidal anti-inflammatory and related nitric oxide-donating drugs. Br J Pharmacol 2002;137:295-310. PMID 12237248

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-COX-inhibiting nitric oxide donators (CINODs), also known as NO-NSAIDs, are a new class of [[NSAID|non-steroidal anti-inflammatory drug]] (NSAID) developed with the intention of providing greater safety than existing NSAIDs. CINODs are hybrid compounds generated by the fusion of an existing NSAID with a [[nitric oxide|nitric oxide]] (NO)-donating [[functional group|moiety]] by chemical means, usually by [[ester#ester reactions|ester linkage]]. CINODs retain the [[anti-inflammatory]] efficacy of NSAIDs ''via'' inhibition of [[cyclooxygenase]] (COX) while arguably improving upon gastric and vascular safety, most likely ''via'' [[vasorelaxation]], inhibition of [[leukocyte]] [[cell adhesion|adhesion]] and reduction of [[apoptosis]], all known effects of NO.
+COX-inhibiting nitric oxide donators (CINODs), also known as NO-NSAIDs, are a new class of [[NSAID|non-steroidal anti-inflammatory drug]] (NSAID) developed with the intention of providing greater safety than existing NSAIDs. These compounds were first described by John Wallace [http://www.ucalgary.ca/irn/wallace.htm] and colleagues. CINODs are hybrid compounds generated by the fusion of an existing NSAID with a [[nitric oxide|nitric oxide]] (NO)-donating [[functional group|moiety]] by chemical means, usually by [[ester#ester reactions|ester linkage]]. CINODs retain the [[anti-inflammatory]] efficacy of NSAIDs ''via'' inhibition of [[cyclooxygenase]] (COX) while arguably improving upon gastric and vascular safety, most likely ''via'' [[vasorelaxation]], inhibition of [[leukocyte]] [[cell adhesion|adhesion]] and reduction of [[apoptosis]], all known effects of NO.
 The first CINODs were developed in the 1990s, and as yet none have been approved for use by the general public. The importance of developing such drugs was increased when [[COX-2 inhibitor|COX-2-specific NSAIDs]] [[rofecoxib]] (Vioxx) and [[lumiracoxib]] (Prexige) were removed from major pharmaceutical markets in the mid-2000s due to [[COX-2 inhibitor#Risks and adverse effects|vascular safety concerns]]. Several CINODs are currently being tested in [[clinical trials]], the most advanced of which are being conducted by the French pharmaceutical company [[NicOx]], whose flagship compound naproxcinod is in [[clinical trials#phase III|phase III trials]] for the treatment of [[osteoarthritis]].[http://www.drugdevelopment-technology.com/projects/azd3582/] Naproxcinod, also known as HCT 3012, AZD3582, NO-naproxen and nitronaproxen, is a fusion of [[naproxen]] and a NO-donating group. Other CINODs are also being tested by NicOx for the treatment of diseases in which inflammation plays a role.[http://www.nicox.com/update/portfolio.html]
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 == References ==
 <references/>
+* Wallace JL, Reuter BK, Cicala C, McKnight W, Grisham MB, Cirino G.  Novel nonsteroidal anti-inflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat.  [[Gastroenterology]] 1994; 107: 172-179. PMID: 8020659
+* Wallace JL, Cirino G.  The development of gastrointestinal-sparing anti-inflammatory drugs.  [[Trends Pharmacol Sci]] 1994; 15: 405-406. PMID: 7855901
 * Keeble JE, Moore PK. Pharmacology and potential therapeutic applications of nitric oxide-releasing non-steroidal anti-inflammatory and related nitric oxide-donating drugs. [[Br J Pharmacol]] 2002;137:295-310. PMID 12237248

v t e Non-steroidal anti-inflammatory drugs (NSAIDs) (primarily M01A and M02A, also N02BA)
pyrazolones / pyrazolidines	Aminophenazone Ampyrone Azapropazone Clofezone Difenamizole Famprofazone Feprazone Kebuzone Metamizole Mofebutazone Morazone Nifenazone Oxyphenbutazone Phenazone Phenylbutazone Propyphenazone Sulfinpyrazone Suxibuzone^‡
salicylates	Aspirin (acetylsalicylic acid)^# Aloxiprin Benorylate Carbasalate calcium Diflunisal Dipyrocetyl Ethenzamide Guacetisal Magnesium salicylate Methyl salicylate Salsalate Salicin Salicylamide Salicylic acid (salicylate) Sodium salicylate
acetic acid derivatives and related substances	Aceclofenac Acemetacin Alclofenac Amfenac Bendazac Bromfenac Bufexamac Bumadizone Diclofenac Difenpiramide Etodolac Felbinac Fenclozic acid Fentiazac Indometacin Indometacin farnesil Isoxepac Ketorolac Lonazolac Mofezolac Oxametacin Prodolic acid Proglumetacin Sulindac Tiopinac Tolmetin Zomepirac^†
oxicams	Ampiroxicam Droxicam Isoxicam Lornoxicam Meloxicam Piroxicam Pivoxicam Tenoxicam
propionic acid derivatives (profens)	Alminoprofen Benoxaprofen^† Carprofen^‡ Dexibuprofen Dexketoprofen Fenbufen Fenoprofen Flunoxaprofen Flurbiprofen Ibuprofen^# Ibuproxam Indoprofen^† Ketoprofen Loxoprofen Miroprofen Naproxen Oxaprozin Pelubiprofen Piketoprofen Pirprofen Suprofen Tarenflurbil Tepoxalin^‡ Tiaprofenic acid Vedaprofen^‡ Zaltoprofen COX-inhibiting nitric oxide donator: Naproxcinod
n-arylanthranilic acids (fenamates)	Azapropazone Clonixin Etofenamate Floctafenine Flufenamic acid Flunixin Flutiazin Glafenine^† Meclofenamic acid Mefenamic acid Morniflumate Niflumic acid Tolfenamic acid
COX-2 inhibitors (coxibs)	Apricoxib Celecoxib (+tramadol) Cimicoxib^‡ Deracoxib^‡ Etoricoxib Firocoxib^‡ Lumiracoxib^† Mavacoxib^‡ Parecoxib Robenacoxib^‡ Rofecoxib^† Valdecoxib^†
other	Aminopropionitrile Benzydamine Chondroitin sulfate Diacerein Fluproquazone Glucosamine Glycosaminoglycan Hyperforin Nabumetone Nimesulide Oxaceprol Proquazone Superoxide dismutase / orgotein Tenidap
NSAID combinations	Ibuprofen/famotidine Ibuprofen/hydrocodone Ibuprofen/oxycodone Ibuprofen/paracetamol Meloxicam/bupivacaine Naproxen/diphenhydramine Naproxen/esomeprazole
Key: underline indicates initially developed first-in-class compound of specific group; ^#WHO-Essential Medicines; ^†withdrawn drugs; ^‡veterinary use.
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