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：
9764847
负责人：
Dorothy Eileen Vatner
金额：
$ 67.34万
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 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764847
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 off-patent preservation pressure reactive hyperemia response therapy design

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 off-patent preservation pressure reactive hyperemia response therapy design

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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.

项目摘要/摘要心肌梗死（MI）治疗的最重要进步是再灌注疗法，这是该疗法必须在进行MI诊断后立即应用。尽管有成千上万的药物研究旨在减少MI大小的疗法，大多数在临床试验中都失败了。我们的假设是主要这些药物失败的原因是必须在治疗性心脏导管插入术之前对其进行施用执行。这显着限制了它们在临床环境中的效用。当前的提议基于腺苷酸环化酶5（AC5）敲除小鼠模型，该模型受到心肌缺血的保护，肥胖，糖尿病，具有比野生类型更长的运动能力和寿命更长。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，因为它们降低了即使在冠状动脉再灌注后施用梗死大小。我们已经开发了一部小说，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抑制剂也无毒。我们在C90上有一项专利，并选择了该化合物进行临床基于功效，药理学和安全性的开发。初步数据表明C90可以减少梗塞在鼠标MI模型中再灌注后施用超过50％后施用大小。该提议的目的是为了获得小鼠的原则证明，渡边兔子有动脉粥样硬化和大型哺乳动物的动物梗塞大小，心脏功能和完整的药理学，ADME和毒理学研究的模型。