Small Molecule Therapeutics for Myocardial Ischemia

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DESCRIPTION (provided by applicant): Left untreated, myocardial ischemia can lead to cardiomyocyte death and pump failure. In fact, myocardial infarction is a significant cause of morbidity and mortality in the U.S. Recent evidence suggests that scatter factor / hepatocyte growth factor, exerts direct protective effects on cardiac myocytes and can potentially be used for salvage of the ischemic myocardium. However the feasibility of using this growth factor in the form of gene or protein therapy is compounded by numerous logistical issues. Using a product discovery engine comprising phage display, 3-dimensional molecular modeling, protein chemistry and preclinical biology, we have identified two distinct chemical classes of SF/HGF-like small molecules. In vitro screening of member compounds led to two distinct lead candidates, one from each chemical class. Phase I studies that these two candidates exert significant protective effects. In this translational Phase II program, we will first make an in- depth comparison of our two small molecule candidates in a rodent model of in vivo myocardial ischemia- reperfusion injury. The single lead candidate emerging from Aim 1 studies will be entered into Aims 2 and 3, which comprise of efficacy studies in clinically relevant models of myocardial ischemic injury. Supported by separate funding, a comprehensive set of studies to characterize the pharmacokinetic, biodistribution, acute safety and safety pharmacology profile of our SF/HGF mimetics is already underway and preliminary results from these studies are extremely encouraging. Together with these ongoing regulatory studies, the proposed efficacy studies will provide sufficient information to submit an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) for initiation of a clinical trial with an SF/HGF mimetic. Myocardial infarction remains a significant cause of morbidity and mortality. A small molecule growth factor therapeutic that is cardioprotective has tremendous clinical benefit.