Novel Coronary Artery Vasodilator Development

新型冠状动脉血管扩张剂的开发

基本信息

批准号：
10758940
负责人：
John Frederick Schmedtje
金额：
$ 30万
依托单位：
COEURATIVE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10758940
关键词：
Adult Affect Age Years Angina Pectoris Animal Model Arteries Atherosclerosis Biological Availability Blood Vessels Cardiac Cardiovascular Diseases Cardiovascular Physiology Cause of Death Cell Hypoxia Cell membrane Cells Cessation of life Chest Pain Cholesterol Chronic Coculture Techniques Coronary Coronary artery Coronary heart disease Country Cyclic GMP Data Death Rate Dermal Development Disease Dose Endothelial Cells Endothelium Endothelium-Dependent Relaxing Factors Enzyme-Linked Immunosorbent Assay Funding Generations Generic Drugs Guanosine Heart High Pressure Liquid Chromatography Human Hypoxia Incubated Individual Isosorbide Isosorbide Dinitrate Link Lung Mediating Medical Modeling Monitor Morbidity - disease rate Movement Myocardial Infarction Nitrates Nitric Oxide Nitric Oxide Donors Non-Insulin-Dependent Diabetes Mellitus Oral Oxygen Pathogenesis Patients Periodicity Pharmaceutical Preparations Phase Physiological Play Prevalence Production Property Quality of life Relaxation Role Second Messenger Systems Signal Transduction Signaling Molecule Small Business Innovation Research Grant Smooth Muscle Myocytes Soluble Guanylate Cyclase Sudden Death Symptoms Tachyphylaxis Testing Therapeutic Time Tissues United States Urea Vascular Endothelial Cell Vascular Endothelium Vascular Smooth Muscle Vasodilator Agents Work analog cGMP production cardioprotection chronic inflammatory disease comparative efficacy coronary vasculature coronary vasodilator design diabetic patient efficacy evaluation efficacy testing improved mitochondrial dysfunction mortality normoxia novel phase 1 study phase 2 study response side effect small molecule symptom treatment therapeutic development

项目摘要

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.

项目摘要：心血管疾病 (CVD) 是全球主要死亡原因，并且据估计，2015 年至 2018 年间，约 1.27 亿美国成年人死亡。某种形式的 CVD 是导致 41% 心绞痛死亡的直接原因。胸痛是冠心病的主要症状，是由心脏供氧失衡引起的胸痛或不适；氧气需求超过其供应。这种缺氧或缺氧与大多数 CVD 的患病率有关。据估计，西方国家 65 岁以上患者中稳定型心绞痛的发生率超过 10% 年死亡率高达3.2%，但冠心病的首发症状可能是猝死。提供一氧化氮 (NO)、初级内皮源性舒张因子 (EDRF) 的血管扩张剂是目前针对症状性心绞痛的首选初始治疗方法有缺点。例如短期疗效、副作用或快速耐受；因此，迫切需要新的治疗方法 Coeurative, Inc. 正在开发新型抗心绞痛药物，以增强 NO 的输送。在第一阶段 SBIR 提案的资助期内，Coeurative, Inc 将描述一类新的一氧化氮 (NO) 供体化合物（CR 化合物）作为新型抗心绞痛药在目标 1 中，这些化合物的血管舒张活性。在目标 2 期间，将使用人类捐赠者的冠状动脉环来建立化合物。 NO 和鸟苷 3',5'-环单磷酸 (cGMP)，在血管生成中发挥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醇-2- 进行比较单硝酸酯 (IS2MN) 和二硝酸异山梨酯 (ISDN)，常规给予的通用 NO 供体作为治疗对于心绞痛，如果作用机制已完成，则拟议工作将扩展到第二阶段研究。 CR化合物的作用将得到进一步阐明，并将其与IS2MN和ISDN在动物中的功效进行比较 CHD 模型。