TY - JOUR AU - Ason, Brandon AU - Chen, Yinhong AU - Guo, Qi AU - Hoagland, Kimberly M. AU - Chui, Ray W. AU - Fielden, Mark AU - Sutherland, Weston AU - Chen, Rhonda AU - Zhang, Ying AU - Mihardja, Shirley AU - Ma, Xiaochuan AU - Li, Xun AU - Sun, Yaping AU - Liu, Dongming AU - Nguyen, Khanh AU - Wang, Jinghong AU - Li, Ning AU - Rajamani, Sridharan AU - Qu, Yusheng AU - Gao, BaoXi AU - Boden, Andrea AU - Chintalgattu, Vishnu AU - Turk, Jim R. AU - Chan, Joyce AU - Hu, Liaoyuan A. AU - Dransfield, Paul AU - Houze, Jonathan AU - Wong, Jingman AU - Ma, Ji AU - Pattaropong, Vatee AU - VĂ©niant, Murielle M. AU - Vargas, Hugo M. AU - Swaminath, Gayathri AU - Khakoo, Aarif Y. T1 - Cardiovascular response to small-molecule APJ activation PY - 2021/02/04/ AB - Heart failure (HF) remains a grievous illness with poor prognosis even with optimal care. The apelin receptor (APJ) counteracts the pressor effect of angiotensin II, attenuates ischemic injury, and has the potential to be a novel target to treat HF. Intravenous administration of apelin improves cardiac function acutely in patients with HF. However, its short half-life restricts its use to infusion therapy. To identify a longer acting APJ agonist, we conducted a medicinal chemistry campaign, leading to the discovery of potent small-molecule APJ agonists with comparable activity to apelin by mimicking the C-terminal portion of apelin-13. Acute infusion increased systolic function and reduced systemic vascular resistance in 2 rat models of impaired cardiac function. Similar results were obtained in an anesthetized but not a conscious canine HF model. Chronic oral dosing in a rat myocardial infarction model reduced myocardial collagen content and improved diastolic function to a similar extent as losartan, a RAS antagonist standard-of-care therapy, but lacked additivity with coadministration. Collectively, this work demonstrates the feasibility of developing clinical, viable, potent small-molecule agonists that mimic the endogenous APJ ligand with more favorable drug-like properties and highlights potential limitations for APJ agonism for this indication. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.132898 VL - 5 IS - 8 UR - https://doi.org/10.1172/jci.insight.132898 PB - The American Society for Clinical Investigation ER -