The goal of this Phase I STTR grant application is to capitalize on our recent discovery of novel sulfide:quinone oxidoreductase (SQOR) inhibitors by the design and preparation of new analogs for the treatment of heart failure that enable us to understand SAR so as to improve potency and optimize ADME/PK properties. Heart failure is a highly lethal disease affecting more than 6 million adults in the United States. Hypertension, myocardial infarction, and ischemia associated with coronary artery atherosclerosis are the leading causes of heart failure. There are presently no effective treatments for heart failure other than heart transplantation, which is limited by the availability of organ donors and immunosuppressive agents. There is an urgent need for novel therapeutics that reduce the major risk factors and prevent the pathological remodeling triggered by myocardial injury that leads to heart failure. The attractiveness of increasing H2S levels as a therapeutic strategy to treat heart failure stems from the ability of this gasotransmitter to activate multiple protective pathways at the same time. Thus, H2S protects against the development of hypertension and atherosclerosis and plays a key role in mitigating pathological remodeling by regulating multiple critical cellular responses including hypertrophy, anti-oxidant, apoptosis, fibrosis, angiogenesis and inflammation. Our therapeutic strategy targets SQOR, an enzyme that sits at a key pharmacological intervention point because it catalyzes the first irreversible step in H2S metabolism. The Phase I objectives will be achieved by combining the biochemical and cell biology expertise of the Jorns group at Drexel University with the pharmaceutical and medicinal chemistry expertise of scientists at the Fox Chase Chemical Diversity Center, Inc. We will accomplish these goals through two specific aims. Aim 1: Perform iterative medicinal chemistry to enhance the potency of SQOR inhibitors to the low nanomolar range and improve drug-like properties with cellular potency for SQOR inhibition of IC50 # 1 ?M and specificity index $ 10. Compounds meeting these criteria will be assessed for their ability to improve survival and reduce apoptosis of cardiomyocytes in an ischemia/reperfusion model and prevent hypertrophy induced by treatment with an adrenergic receptor agonist. Our goal is to achieve these criteria while removing the unwanted functionalities present in some of the original hits. We will synthesize 50-60 new analogs based on existing inhibitor scaffolds, and expect to find at least 10 SQOR inhibitors that meet the criteria of this aim. Aim 2: Evaluate ADME/PK properties for compounds meeting the desired criteria for biochemical and cellular potency. We will explore potential probe- and drug-like suitability by evaluating ~3-4 top leads in assays measuring microsomal stability, plasma protein binding, Cyp3A4 inhibition, aqueous solubility and cell permeability (Caco-2 assay). The most promising 1-3 compounds will also be evaluated for their pharmacokinetic properties in mice. Successful completion of these objectives will uniquely position us to execute an expanded drug discovery program directed against SQOR in a Phase II period of study to include efficacy evaluation in a mouse model for pressure overload-induced heart failure.