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）是全球死亡的主要原因，是在美国负责三分之一的死亡。据估计，在2015年至2018年之间，约有1.27亿美国成年人某种形式的CVD。冠状动脉疾病（CHD）直接造成约41％的CVD死亡。心绞痛 pecoris是冠心病的主要症状，是由氧气失衡引起的胸痛或不适。心的氧气需求超过其供应。这种缺氧或缺氧与大多数CVD有关。流行率西方国家的稳定心绞痛的胸肌估计在65岁以上的患者中超过10％年死亡率高达3.2％，但CHD的第一个症状可能是猝死。抗原捐赠一氧化氮（NO）的血管扩张剂，主要内皮衍生的放松因子（EDRF）是首选有症状性心绞痛的初始治疗。当前没有基于基于的反对派人士有缺点例如短期有效性，副作用或速度；因此，迫切需要新颖的治疗用于心绞痛。 Coeurative，Inc。正在开发新型的抗原，以增强无递送。在 I阶段I SBIR提案的资金期限，Coeurative，Inc将表征新的一氧化氮（NO）供体化合物（CR化合物）作为新型抗教徒。在AIM 1中，这些活性将使用人类供体的冠状动脉环建立化合物。在目标2期间，生产 NO和鸟嘌呤3'，5'周期单磷酸盐（CGMP），第二个使者在血管中起着至关重要的作用通过CR化合物将平滑肌（和血管）松弛与异氧化物-2-- 单硝酸盐（IS2MN）和异氧化脱酸（ISDN），通用捐赠者常规施用作为治疗对于心绞痛。拟议工作的完成将扩展到第二阶段研究，其中作用机理 CR化合物的效率将进一步阐明，与动物中的IS2MN和ISDN相比，它们的效率 CHD的模型。