Nicox has synthetized several new NO-releasing compounds. NCX 4016, an acetyl salicylic acid derivative containing a nitric oxide-releasing moiety is one of the most studied. NCX 4016 possesses a broad spectrum of antithrombotic and antiinflammatory activities. Furthermore accumulating evidence indicates that the NO-releasing part confers a number of pharmacological effects as compared to the parent compound.
Nicox will make available one or more of its compound, for exemple NCX 4016, as a pharmacological tool to test the models and assess the contribution of NO in different pathological settings. NicOx research programs include NO-releasing compounds targeted to improve endothelial dysfunction associated with cardiovascular disorders. Throughout the duration of the present project, Nicox will evaluate whether one of such new compounds will improve the pharmacological profile compared with the prototype NCX 4016.
Moreover, in Nicox labs the amount and kinetics of NO release in biological samples by using different approaches such as electron paramagnetic resonance (EPR) spectroscopy or measurement of cyclicGMP accumulation in tissues or cell lines will be evaluated.
NCX 4016 and cardiovascular diseases: a potential field of application
NCX 4016, a NO-donating derivative of acetyl
salicylic acid (ASA, the active ingredient in aspirin) is currently 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
Phase I gastro-intestinal safety data for NCX 4016 show an excellent gastric
safety profile compared with aspirin (Fiorucci et al., Gastroenterology
2003, 124; 600-607). Its inhibitory effects on platelet aggregation and
thromboxan match that of aspirin, while preventing the development of haemorrhagic
lesions or stomach and duodenum ulcers commonly seen with aspirin.
NCX 4016 has received an IND in the US in October 2002 allowing the product
to enter into Phase IIa in arterial occlusive diseases.
This set of results confirms the potential of NCX 4016 in the prevention
and treatment of cardiovascular diseases.
Vision for the future
NCX 4016 is being studied clinically to assess its profile in cardiovascular disorders. The overall objective is to achieve an NDA and make the drug available to patients
Other NO-releasing compounds are being exanimate in experimental models. One class deserving to be mentioned and of interest for the program is that of nitrostatins. These compounds have shown, besides the cholesterol lowering, additional anti-inflammatory properties combined with antiplatelet / antithrombotic activity. Thus, they represent an interesting class of drugs with therapeutic potential in disorders associated with endothelial dysfunction and vascular inflammation.
References
1. Muscara M., McKnight W., Del Soldato P., Wallace J., Lovren F., Dicay M., Triggle C. Vasorelaxant effects of a nitric oxide-releasing aspirin derivative in normotensive and hypertensive rats. Br J Pharmacol. 2001, 133: 1314-1322.
2. Rossoni G., Manfredi B., De Gennaro Colonna V., Bernareggi M., Berti F. The nitroderivative of aspirin, NCX 4016, reduces infarct size caused by myocardial ischemia/reperfusion in the anasthetized rat. J. Pharmacol. Exp. Ther., 2001, 297: 380-387.
3. Fiorucci S, Mencarelli A, Mannucci R, Distrutti E, Morelli A, Del Soldato P, Moncada S. NCX-4016, a nitric oxide-releasing aspirin, protects endothelial cells against apoptosis by modulating mitochondrial function. FASEB J. 2002, 16: 1645-1647.
4. Fiorucci S., Santucci L., Gresele P., Maffei Faccino R., Del Soldato P. and Morelli A. Gastrointestinal safety of NO-Aspirin (NCX 4016) in healthy human volonteers: a proof of concept endoscopic study. Gastroenterology, 2003, 124: 600-607.
5. Ongini E., Impagnatiello F., Bonazzi A., Guzzetta M., Govoni M., Monopoli A., Del Soldato P., Ignarro L.J. Nitric-oxide (NO)-releasing statin derivatives, a new class of drugs showing enhanced antiproliferative and anti-inflammatory properties. Proc. Nat. Acad. Sci. USA, 2004, 101: 8497-8502.
6. Iwanaga Y., Gu Y., Dieterle T., Presotto C., Del Soldato P., Peterson K.L., Ongini E., Condorelli G., Ross J. Jr., A nitric-oxide-releasing derivative of enalapril, NCX 899, prevents progressive cardiac dysfunction and remodeling in amster with heart failure. FASEB J., 2004, 18: 587-588.
7. Fiorucci S., Distrutti E., Mencarelli A., Rizzo G., Di Lorenzo A.R., Baldoni M., Del Soldato P., Morelli A. Wallace J.L. Cooperation between aspirin-triggered lipoxin and nitric oxide (NO) mediates antiadhesive properties of 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX 4016) (NO-aspirin) on neutrophil-endothelial cell adherence. J. Pharmacol. Exp. Ther., 2004, 309: 1174-1182.
8. Di Filippo C., Rossi F., Ongini E.
Del Soldato P., Perretti M., D’Amico M. The distinct alterations produced
in cardiovascular functions by prednisolone and nitroprednisolone (NCX 1015)
in the rat highlight a casual role for endothelin-1. J. Pharmacol. Exp.
Ther., 2004, in press.