PROJECT SUMMARY/ABSTRACT. This SBIR proposes development of a new drug for treatment of heart failure, a disease currently responsible for the deaths of ~80,000 people annually in the US. The underlying causes of this condition include myocardial infarction, hypertension and disease of the heart valves. Existing treatments primarily act on the neurohormonal axis to reduce volume overload but despite the availability of these drugs, 5-year mortality following a heart failure diagnosis is approximately 50% and is similar to many cancers. We propose to develop a drug that directly targets cardiac metabolism, reversing the reduced use of fat oxidation that occurs in the failing heart and thereby enabling it to maintain its pump function. This will be achieved by drugs that activate estrogen-related receptors (ERRs), a type of nuclear receptor that regulates mitochondrial energy metabolism. There are 3 isoforms of estrogen-related receptors – a, b and g. We have generated data to show that ERR agonists that activate all 3 isoforms protect against the decline in heart function that occurs in the transaortic constriction (TAC) model in the mouse. In this Phase I application we propose to identify agonists that selectively activate individual isoforms (or combinations thereof) and test their effects in the TAC model in order to delineate the isoforms mediating benefit in heart failure. We have selected a short-list of potentially useful tools from the ~560 proprietary compounds that have already been made and will profile them in vitro and in vivo to identify those suitable to be tested in the TAC model. In the course of this work, we will also validate isoform-specific genetic biomarkers for their ability to confirm the activation of the specific isoforms after in vivo dosing of compounds. In Phase II we will use the knowledge gained in Phase I to develop more potent and drug-like ERR agonists, nominate a clinical development candidate and characterize its properties more fully, including in heart failure models other than the TAC model. If successful we hope to improve the survival and quality of life of heart failure patients and save a significant proportion of the 1-2% of health care expenditure that is currently spent treating this condition.