PROJECT SUMMARY/ABSTRACT Heart failure is a major cause of morbidity and mortality in the population, with rising incidence of cardiovascular disease contributed to by epidemic increases in obesity and associated type 2 diabetes mellitus. Although existing drugs are effective in acutely correcting decompensated heart failure, this continues to be associated with unacceptable rates of rehospitalization and mortality. A drug combination adding neprilysin inhibition to the previous standard-of-care for heart failure, angiotensin receptor blockade, was recently approved by the FDA based on its ability to extend the life of patients with reduced cardiac output. However, the broad action of the peptidase inhibitor in this combination could theoretically be improved, thereby reducing possible side effects and increasing therapeutic effectiveness. The specific enzyme substrate responsible for the beneficial effects of this drug is not yet clear. While it has been assumed to be natriuretic peptides, other peptides are also cleaved by neprolysin, many of which have potential offsetting and/or side effects. Another prominent potentially beneficial substrate of this protease is secretin, a peptide hormone with useful effects on cardiac contractility and ejection fraction, coronary perfusion, peripheral vascular resistance, post-cibal satiety, and glucose-sensitive incretin action. Prior to work supported by this grant in its previous funding cycle, there were no small molecules known to mimic or enhance secretin activity at its receptor. In that work, we screened nearly 400,000 compounds and identified several structural classes of compounds that demonstrate robust and reproducible activation of secretin receptor signaling in vitro in model cell systems. As a continuation of those encouraging data, we now propose to utilize medicinal chemical approaches to optimize the scaffolds identified in the previous work. These include compounds with the ability to act as positive allosteric modulators of secretin action, as well as those having intrinsic agonist activity. We will utilize cycles of systematic chemical modification and rational enhancement with in vitro pharmacologic characterization to improve their pharmacological and ADME/T properties (Aims 1 and 2). The best candidates in each structural series will be studied using in vivo animal models to evaluate their oral bioavailability and efficacy, as well as an in vivo rat model of ischemic heart failure (Aim 3). Our approach will validate this receptor as an attractive target for therapeutic intervention in heart failure and provide first-in-class small molecule compounds that we hope to take into clinical trials in the future.