Phase II year
2019
(last award dollars: 2020)
Phase II Amount
$1,388,427
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.
Public Health Relevance Statement: PROJECT NARRATIVE Despite the advances in the treatment of Acute MI and Heart Failure (HF) over the past several decades, these diseases are the most significant health concerns in the U.S. The most important therapy is to open the occluded coronary artery by catheterization when the patient with MI enters the hospital. The goal of this research is to develop a new drug that when administered after the artery is opened reduces damage and helps to preserve recovery of myocardial function, protecting against the development of heart failure.
NIH Spending Category: Aging; Atherosclerosis; Cardiovascular; Heart Disease; Heart Disease - Coronary Heart Disease
Project Terms: Acute myocardial infarction; Adenine; Adenosine; adenylyl cyclase type V; Adverse effects; Animal Model; Animals; Arteries; Atherosclerosis; base; Benchmarking; Biological Assay; Cardiac; Cardiac Catheterization Procedures; Cardiac Output; cardiogenesis; cardioprotection; Cardiotonic Agents; Catheterization; Cells; Chronic; Clinic; Clinical; clinical development; clinical practice; Clinical Trials; Conscious; Coronary Arteriosclerosis; Coronary artery; coronary artery occlusion; Data; Diabetes Mellitus; Diagnosis; Disadvantaged; Disease; Dose; Enzymes; Exercise; exercise capacity; Family suidae; Goals; Health; Healthcare; Heart; Heart Diseases; Heart failure; heart function; Heart Rate; hemodynamics; Hospitals; Hypotension; improved; In Vitro; Infarction; inhibitor/antagonist; Institutes; instrument; Knock-out; Knockout Mice; Left Ventricular Ejection Fraction; Left Ventricular Function; Legal patent; Longevity; Malignant Neoplasms; Mediating; MEKs; Minor; Modeling; mortality; mouse model; Mus; Myocardial; myocardial infarct sizing; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; novel; novel therapeutics; nucleoside analog; Obesity; off-patent; Oryctolagus cuniculus; Oxidative Stress; Pathway interactions; Patient Care; Patients; Performance; Peripheral Resistance; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; preservation; pressure; Publishing; reactive hyperemia; Recovery; Reperfusion Therapy; Research; response; Safety; Tachycardia; Testing; Therapeutic; therapy design; Time; Toxic effect; Toxicology; Translating; Work
