Cardiovascular response to small-molecule APJ activation

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Abstract

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.

Authors

Brandon Ason, Yinhong Chen, Qi Guo, Kimberly M. Hoagland, Ray W. Chui, Mark Fielden, Weston Sutherland, Rhonda Chen, Ying Zhang, Shirley Mihardja, Xiaochuan Ma, Xun Li, Yaping Sun, Dongming Liu, Khanh Nguyen, Jinghong Wang, Ning Li, Sridharan Rajamani, Yusheng Qu, BaoXi Gao, Andrea Boden, Vishnu Chintalgattu, Jim R. Turk, Joyce Chan, Liaoyuan A. Hu, Paul Dransfield, Jonathan Houze, Jingman Wong, Ji Ma, Vatee Pattaropong, Murielle M. Véniant, Hugo M. Vargas, Gayathri Swaminath, Aarif Y. Khakoo