Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C16H13NO7 |
| Molecular Weight | 331.2769 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CC(=O)OC1=CC=CC=C1C(=O)OC2=CC(CO[N+]([O-])=O)=CC=C2
InChI
InChIKey=IOJUJUOXKXMJNF-UHFFFAOYSA-N
InChI=1S/C16H13NO7/c1-11(18)23-15-8-3-2-7-14(15)16(19)24-13-6-4-5-12(9-13)10-22-17(20)21/h2-9H,10H2,1H3
| Molecular Formula | C16H13NO7 |
| Molecular Weight | 331.2769 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
NCX-4016, a nitric oxide non-steroidal anti-inflammatory drug (NO-NSAID) which can inhibit cyclooxygenase as well as release nitric oxide, is under development by NicOx as a potential treatment for thrombosis, inflammation and rheumatoid arthritis. NCX-4016 possesses a broad spectrum of antithrombotic and antiinflammatory activities. NCX-4016 has been shown to inhibit platelet activation in vitro more effectively than aspirin, to inhibit smooth muscle cell proliferation, to exert an endothelial cell protective activity and to suppress the function of several inflammatory cells potentially involved in atherothrombosis. In animal models, NCX-4016 protected from platelet thromboembolism, prevented restenosis in atherosclerosis-prone animals, protected the heart from ischemia/reperfusion injury, and induced neoangiogenesis in critically ischemic limbs. Moreover, it displayed little or no gastric toxicity and appeared to protect stomach from noxious stimuli, including aspirin. NCX-4016 has been evaluated in healthy volunteers and found to inhibit platelet cyclo-oxygenase-1 (COX-1) similarly to or slightly less than aspirin, to raise the circulating levels of NO-degradation products, and to have little or no gastric toxicity in short term studies. NCX-4016 was in Phase II clinical trials for the treatment of vascular disorders such as peripheral vascular disease and other cardiovascular diseases including thrombosis, complications of endothelium-related diseases such as diabetes and other. But this research was discontinued.
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL221 |
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Target ID: GO:0070527 |
39.0 µM [IC50] | ||
Target ID: GO:0038193 |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | Unknown Approved UseUnknown |
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| Primary | Unknown Approved UseUnknown |
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| Primary | Unknown Approved UseUnknown |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
161.94 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15063462 |
1600 mg single, oral dose: 1600 mg route of administration: Oral experiment type: SINGLE co-administered: |
NCX 4015 plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
784.85 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15063462 |
1600 mg single, oral dose: 1600 mg route of administration: Oral experiment type: SINGLE co-administered: |
NCX 4015 plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
3.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15063462 |
1600 mg single, oral dose: 1600 mg route of administration: Oral experiment type: SINGLE co-administered: |
NCX 4015 plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
PubMed
| Title | Date | PubMed |
|---|---|---|
| NCX-4016 (NO-aspirin) inhibits lipopolysaccharide-induced tissue factor expression in vivo: role of nitric oxide. | 2002 Dec 10 |
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| Implications of reactive oxygen species and cytokines in gastroprotection against stress-induced gastric damage by nitric oxide releasing aspirin. | 2003 Jul |
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| Nitric oxide-donating aspirin inhibits beta-catenin/T cell factor (TCF) signaling in SW480 colon cancer cells by disrupting the nuclear beta-catenin-TCF association. | 2003 Oct 28 |
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| Nitric oxide-releasing aspirin protects gastric mucosa against ethanol damage in rats with functional ablation of sensory nerves. | 2003 Sep |
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| Nitric oxide-releasing aspirin inhibits vasoconstriction in perfused tail artery of normotensive and spontaneously hypertensive rats. | 2003 Sep 5 |
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| NO-donating aspirin inhibits intestinal carcinogenesis in Min (APC(Min/+)) mice. | 2004 Jan 16 |
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| Nitric oxide-releasing aspirin derivative, NCX 4016, promotes reparative angiogenesis and prevents apoptosis and oxidative stress in a mouse model of peripheral ischemia. | 2004 Nov |
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| Nitroaspirin plus clopidogrel versus aspirin plus clopidogrel against platelet thromboembolism and intimal thickening in mice. | 2005 Mar |
|
| NO-donating aspirin inhibits both the expression and catalytic activity of inducible nitric oxide synthase in HT-29 human colon cancer cells. | 2005 Oct 1 |
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| NO-releasing aspirin exerts stronger growth inhibitory effect on Barrett's adenocarcinoma cells than traditional aspirin. | 2006 Dec |
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| Nitric oxide-donating aspirin inhibits colon cancer cell growth via mitogen-activated protein kinase activation. | 2006 Jan |
|
| Nitric oxide-releasing aspirin and indomethacin are potent inhibitors against colon cancer in azoxymethane-treated rats: effects on molecular targets. | 2006 Jun |
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| Quinone formation as a chemoprevention strategy for hybrid drugs: balancing cytotoxicity and cytoprotection. | 2007 Dec |
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| Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats. | 2007 Sep |
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| Induction of paraoxonase 1 and apolipoprotein A-I gene expression by aspirin. | 2008 Oct |
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| Nitro-aspirin inhibits MCF-7 breast cancer cell growth: effects on COX-2 expression and Wnt/beta-catenin/TCF-4 signaling. | 2009 Nov 15 |
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| Hyperglycemia-induced platelet activation in type 2 diabetes is resistant to aspirin but not to a nitric oxide-donating agent. | 2010 Jun |
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| NCX-1000, a nitric oxide-releasing derivative of UDCA, does not decrease portal pressure in patients with cirrhosis: results of a randomized, double-blind, dose-escalating study. | 2010 May |
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| NO-donating aspirin and aspirin partially inhibit age-related atherosclerosis but not radiation-induced atherosclerosis in ApoE null mice. | 2010 Sep 21 |
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| Nitric oxide (NO)-releasing aspirin exhibits a potent esophagoprotection in experimental model of acute reflux esophagitis. Role of nitric oxide and proinflammatory cytokines. | 2011 Feb |
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| Nitro-aspirin is a potential therapy for non alcoholic fatty liver disease. | 2011 Jun 1 |
|
| Nitric oxide-releasing aspirin but not conventional aspirin improves healing of experimental colitis. | 2011 Sep 28 |
Patents
Sample Use Guides
NCX-4016 800 mg b.i.d. for 6 months on top of aspirin 100 mg o.d.
Route of Administration:
Oral
| Substance Class |
Chemical
Created
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admin
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| Record UNII |
EH04H13L6B
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| Record Status |
Validated (UNII)
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| Related Record | Type | Details | ||
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METABOLITE -> PARENT |
The results relative to i.p. administration show a more pronounced and rapid NO delivery (peak of both NOx and RS-NO at 1 h and plateau between 1 and 2 h), still coincident with the peak of SA, and the presence in plasma of NCX 4015 (a metabolite of NCX 4016 which still bears the nitrate function). In myocardial tissue from p.o. treated rats, no drug or metabolites were ever detected, and the NOx levels were always in the range of the controls.
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| Related Record | Type | Details | ||
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ACTIVE MOIETY |
French company NicOx announced that it and the U.S. National Cancer Institute (NCI) have ended an NCI-sponsored Phase I trial studying the potential of NCX 4016 as a preventative treatment for colon cancer. The company said it would delay the start of planned Phase II studies of NCX 4016 for Type 2 diabetes pending the completion of additional testing on NCX 4015.
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ACTIVE MOIETY |
To check the stability of NCX 4016 in the acidic gastric milieu and to explain the different distribution of the drug following p.o. or i.p. administration, the gastric content of the orally-treated animals at different post-dosing times was analysed by HPLC. The unchanged drug was detected up to 8 h post-dosing (levels slowly decreased with time), and the only metabolite to be detected was the O-deacetylated derivative (NCX 4023), which was present in low concentrations up to 4 h post-dosing. This indicates that NCX 4016 does not undergo biotransformation in the upper part of gastrointestinal tract (no direct release of NO in this district) and that the stomach acts as a reservoir for the drug.
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ACTIVE MOIETY |
Class: Analgesic, Antiplatelet, Benzoic acid, Nonsteroidal anti-inflammatory, Small molecule, Vasodilator; Mechanism of Action: Cyclooxygenase inhibitor, Nitric oxide donor, Nitric oxide stimulant and Platelet aggregation inhibitor; Highest Development Phases: Discontinued for Pain, Peripheral arterial occlusive disorders and Type 2 diabetes mellitus; Most Recent Events: 03 Mar 2008 Discontinued - Phase-II for Type-2 diabetes mellitus in Italy (PO), 03 Mar 2008 Discontinued - Phase-II for Type-2 diabetes mellitus in Switzerland (PO)
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