Novel Coronary Artery Vasodilator Development

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PROJECT SUMMARY: Cardiovascular diseases (CVD) are the leading cause of death globally, and are responsible for 1 in 3 deaths in the US. It is estimated that between 2015 and 2018, ~127 million US adults had some form of CVD. Coronary heart disease (CHD) is directly responsible for ~41% of CVD deaths. Angina pectoris, a primary symptom of CHD, is chest pain or discomfort caused by an imbalance of oxygen; the heart’s oxygen demand exceeds its supply. This oxygen deficiency, or hypoxia, is linked to most CVD. The prevalence of stable angina pectoris in Western countries is estimated to be over 10% in patients over 65 years of age with an annual mortality rate of up to 3.2%, but the first symptom of CHD can be sudden death. Antianginal vasodilators that donate nitric oxide (NO), the primary endothelium-derived relaxing factor (EDRF), are the preferred initial treatment for symptomatic angina pectoris. Current NO-based antianginals have shortcomings such as short-term efficacy, side effects, or tachyphylaxis; therefore, there is an urgent need for novel treatments for angina pectoris. Coeurative, Inc. is developing novel antianginals for enhanced NO delivery. During the funding period of this Phase I SBIR proposal, Coeurative, Inc will characterize a new class of nitric oxide (NO) donor compounds (CR compounds) as novel antianginals. In Aim 1, the vasorelaxant activity of these compounds will be established using coronary artery rings from human donors. During Aim 2, the production of NO and guanosine 3’,5’-cyclic monophosphate (cGMP), a second messenger that plays a critical role in vascular smooth muscle (and blood vessel) relaxation, by CR compounds will be compared to that of isosorbide-2- mononitrate (IS2MN) and isosorbide dinitrate (ISDN), generic NO donors routinely administered as treatments for angina. The completion of the proposed work will extend to Phase II studies wherein the mechanism of action of CR compounds will be further elucidated, and their efficacy compared to that of IS2MN and ISDN in an animal model of CHD.