Novel Coronary Artery Vasodilator Development

项目摘要：心血管疾病(CVD)是全球主要的死亡原因， 在美国，三分之一的死亡都要对此负责。据估计，2015至2018年间，约1.27亿美国成年人患有 某种形式的脑血管疾病。冠心病(CHD)直接导致约41%的心血管疾病死亡。心绞痛 胸痛是冠心病的一个主要症状，是由于氧气失衡引起的胸痛或不适；心脏的 氧气需求量超过了供给量。这种缺氧或缺氧与大多数心血管疾病有关。流行率 据估计，在西方国家，65岁以上的患者患稳定型心绞痛的比例超过10% 每年的死亡率高达3.2%，但CHD的首发症状可能是猝死。抗心绞痛 提供一氧化氮(NO)的血管扩张剂，是主要的内皮衍生松弛因子(EDRF)，是 首选对症状性心绞痛的初始治疗。目前的NO类抗心绞痛药物存在不足 如短期疗效、副作用或快速反应；因此，迫切需要新的治疗方法 治疗心绞痛。Coeurative，Inc.正在开发用于增强NO释放的新型抗心绞痛药物。在.期间 第一阶段SBIR提案的资助期，Coeurative，Inc.将表征一种新的一氧化氮(NO) 作为新型抗心绞痛药的供体化合物(CR化合物)。在目标1中，这些化合物的血管松弛活性 化合物将使用来自人类捐赠者的冠脉环来建立。在Aim 2期间，制作了 NO和鸟苷3‘，5’-环单磷酸(CGMP)，这是在血管中起关键作用的第二信使 CR化合物的平滑肌(和血管)松弛作用将与异山梨酯-2-松弛作用进行比较。 单硝酸酯(IS2MN)和硝酸异山梨酯(ISDN)，作为常规治疗的通用NO供体 治疗心绞痛。拟议工作的完成将延伸到第二阶段研究，其中行动机制 将进一步阐明CR化合物的有效性，并将其与IS2MN和ISDN在动物身上的疗效进行比较 冠心病模型。

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.