Identification of Novel and Selective GPR39 Receptor Antagonists for the Treatment of Acute Myocardial Ischemia

Following up on the discovery of multiple series of GPR39 antagonists via high-throughput screening (HTS), appropriate hit expansion and medicinal chemistry efforts lead to the identification of potent and selective GPR39 antagonists. Among these, compound 61 emerges as the front runner of this series, demonstrating high potency, appropriate physicochemical properties governing systemic exposure, in both rat and dog, and the absence of undesired off-target pharmacology such as cardiac ion channels (i.e., hERG, hNav1.5, and Cav1.2). In vivo evaluations show compound 61 to be a selective coronary vasodilator that reduced no-reflow and infarct size in a rodent model of ischemia-reperfusion. This first-in-class drug demonstrates the benefit of GPR39 inhibition in myocardial ischemia.