Developing Small Molecule Therapies for Heart Failure

ABSTRACT Heart failureHFis a major cause of morbidity and mortality in the United StatesWhile progress in conventional treatments is making steady and incremental gains to reduce HF mortalitythere is a critical need to explore new therapeutic approachesHuman and experimental models of HF revealed that a major defect in HF is the reduced expression and altered activity of the cardiac sarcoplasmic reticulumSRCaATPaseSERCA aIn factgenetic overexpression of SERCA a significantly rescued HF phenotypes and increased animal survivalThereforetargeting dysfunctional SERCA a with small molecule drugs that directly activate native SERCA a pump is a persuasive strategy to treat HFIn this proposalwe aim to benchmark and test a newly discovered SERCAallosteric activatorCDNin HF mouse modelsCDNdirectly binds to and triggers intrinsic activation of SERCA aPreliminary results in animal models of diabetes show significant improvement in cardiomyocyte contractility and cardiac dysfunction in vivoWe expect toDetermine whether activation of SERCA a correlates with a decrease in HF associated contractile impairmentandIdentify a set of compounds suitable for further development as drugs to treat HFIn this PhaseSBIR applicationwe will use medicinal chemistry to optimize the potencyand develop the structure activity relationshipsSARof our most promising lead compounds based on contractile function in isolated myocytes in vitroand functional testing in a rodent model of HF in vivoOur goal in SUMOCOR LLC is to provide druglike compounds suitable for development as novel therapeutic potential to treat HF PROJECT NARRATIVE We aim to develop heart failureHFtherapies that increase Calcium uptake from the myocyte cytoplasm into the sarcoplasmic reticulumSRA key abnormality in both experimental and human HF is a defect in SR functionwhich is associated with the decreased expression and activity of the SR Ca ATPaseSERCA athe membrane enzyme that pumps Cainto the SR lumen to relax muscleOur goal is to discover and test novel drugs that activate SERCA a as a therapeutic means to treat HF