The objective of this research is the identification of compounds that may decrease damage to myocardial tissue following a myocardial infarction (MI). Specifically, the investigators seek to identify compounds which reduce oxidative stress and calcium loading immediately after MI. In this Phase I application, the investigators propose to use in vitro screens of hypoxia and calcium loading to select compounds for evaluation in rat models of transient and permanent myocardial infarction. Confocal microscopy will be used in conjunction with the in vitro screens to evaluate cellular calcium influx. The results of these experiments will set the stage for the Phase II evaluations of structure and activity, and for the synthesis of compounds designed to have the appropriate balance of properties for MI treatment. One hundred twenty candidate compounds will be selected from Centaur's compound library using specified criteria. These compounds will be screened using in vitro hypoxia reoxygenation and A23187-induced rat myocardial cell (H9C2) toxicity assays. Tests will evaluate the effect of compounds added to the in vitro system both before hypoxia and at the point of reoxygenation. For the 12 best compounds from the in vitro testing, intracellular calcium concentration dynamics will be assessed at LSU using confocal microscopy. The three most promising compounds from the in vitro assays and confocal microscopy examination will be tested in a rat transient coronary artery occlusion model. The best single compound will be tested in a rat permanent coronary artery occlusion model, and confocal microscopy will be utilized to characterize the mechanism of action of the compound. Finally, the best compound will serve as the lead for optimization of physical, chemical, and biological properties in the Phase II SBIR.
The National Heart, Lung and Blood Institute estimates that there are 1.25 million heart attacks per year in the US, with about two-thirds representing first attacks and one-third recurrent attacks. Heart attacks are the number on cause of death in western societies and result in 500,000 deaths annually in the US. Over six million Americans have some form of coronary heart disease that makes them susceptible to heart attacks. Medical costs associated with coronary heart disease are about $80 billion in the US, about 15% of the annual health care budget. Based on the therapeutic success of Centaur's proprietary compounds in the treatment of cerebral stroke, there is a good likelihood that these compounds can help protect the heart from the damage caused by the ischemia and inflammation that accompanies a heart attack. This effect would improve patient outcomes and reduce the incidence of mortality from heart attacks.