Adenylyl Cyclase Type 5 Inhibition to Treat Myocardial Infarction

腺苷酸环化酶 5 型抑制治疗心肌梗死

基本信息

批准号：
9918966
负责人：
Peter Golikov
金额：
$ 71.5万
依托单位：
VASADE BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918966
关键词：
Acute myocardial infarction Adenine Adenosine Adverse effects Animal Model Animals Arteries Atherosclerosis Benchmarking Biological Assay Cardiac Cardiac Catheterization Procedures Cardiac Output Cardiotonic Agents Catheterization Cells Chronic Clinic Clinical Clinical Trials Conscious Coronary Arteriosclerosis Coronary artery Data Diabetes Mellitus Diagnosis Disadvantaged Disease Dose Enzymes Exercise Family suidae Goals Health Healthcare Heart Heart Diseases Heart Rate Heart failure Hospitals Hypotension In Vitro Infarction Institutes Knock-out Knockout Mice Left Ventricular Ejection Fraction Left Ventricular Function Legal patent Longevity MEKs Malignant Neoplasms Mediating Minor Modeling Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Obesity Oryctolagus cuniculus Oxidative Stress Pathway interactions Patient Care Patients Performance Peripheral Resistance Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Publishing Recovery Reperfusion Therapy Research Safety Tachycardia Testing Therapeutic Time Toxic effect Toxicology Translating Work adenylyl cyclase type V base cardiogenesis cardioprotection clinical development clinical practice coronary artery occlusion exercise capacity heart function hemodynamics improved inhibitor/antagonist instrument mortality mouse model myocardial infarct sizing novel novel therapeutics nucleoside analog preservation pressure reactive hyperemia response therapy design

项目摘要

PROJECT SUMMARY/ABSTRACT The most significant advance in the treatment of Myocardial Infarction (MI) has been reperfusion therapy, which must be applied immediately after the MI diagnosis has been made. Despite the thousands of studies on drug therapies designed to reduce the size of the MI, most have failed in clinical trials. Our hypothesis is that a major reason why these drugs failed is that they must be administered before therapeutic cardiac catheterization is performed. This significantly limits their utility in the clinical setting. The current proposal is based on studies in the Adenylyl Cyclase type 5 (AC5) knock out mouse model, which is protected against myocardial ischemia, obesity, diabetes and has enhanced exercise capacity and lives longer than wild type. Our preliminary data demonstrate that pharmacological inhibitors of the AC5 enzyme have a unique advantage in that they reduce infarct size even when administered after coronary reperfusion. We have developed a novel, more potent and more selective AC5 inhibitor, C90, which is particularly attractive because it is a potent non-nucleoside adenine AC5 inhibitor and also is not toxic. We have a patent pending on C90 and selected this compound for clinical development based on efficacy, pharmacology and safety. Preliminary data indicate that C90 can reduce infarct size when administered after reperfusion by more than 50% in a mouse MI model. The goal of this proposal is to obtain proof-of-principle in mice, in Watanabe rabbits with atherosclerosis and in a large mammalian animal model for infarct size, cardiac function and complete IND-enabling pharmacology, ADME and toxicology studies.

项目概要/摘要心肌梗死 (MI) 治疗中最显着的进展是再灌注治疗，必须在 MI 诊断做出后立即应用。尽管有数千项关于药物的研究旨在缩小心梗范围的疗法大多数在临床试验中都失败了。我们的假设是一个主要的这些药物失败的原因是它们必须在治疗性心导管插入术之前施用执行。这极大地限制了它们在临床环境中的效用。目前的提案基于以下研究： 5 型腺苷酸环化酶 (AC5) 敲除小鼠模型，可防止心肌缺血，肥胖，糖尿病，运动能力增强，寿命比野生型更长。我们的初步数据证明 AC5 酶的药理学抑制剂具有独特的优势，因为它们可以减少即使是在冠状动脉再灌注后给药，梗塞面积也会受到影响。我们开发了一种新颖的、更有效的更具选择性的 AC5 抑制剂 C90，它特别有吸引力，因为它是一种有效的非核苷腺嘌呤 AC5抑制剂也没有毒性。我们正在申请 C90 专利，并选择该化合物用于临床基于功效、药理学和安全性的开发。初步数据表明C90可以减少梗塞在小鼠 MI 模型中，再灌注后给药时的大小超过 50%。该提案的目标是在小鼠、患有动脉粥样硬化的渡边兔和大型哺乳动物中获得原理验证用于梗塞面积、心脏功能和完整的 IND 药理学、ADME 和毒理学研究的模型。