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 HF patients. 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 two 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 co-administration. 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 highlight potential limitations for APJ agonism for this indication.
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 C. Y. Chan, Liaoyuan A. Hu, Paul Dransfield, Jonathan B. Houze, Jing Man Wong, Ji Ma, Vatee Pattaropong, Murielle M. Veniant, Hugo M Vargas, Gayathri Swaminath, Aarif Khakoo
Guidelines: The Editorial Board will only consider letters that we deem relevant and of interest to our readers. We will not post data that have not been subjected to peer review, nor will we post letters that are essentially a reiteration of another letter. We reserve the right to edit any letter for length, content, and clarity. Authors will be notified by e-mail if their letters were accepted. No appeals will be considered.
Specific requirements: All letters must be 400 words or fewer. You may enter the letter as plain text or HTML. The author's name and e-mail address are required, and will be posted with the letter. All possible conflicts of interest must be noted, even if they are not posted. If you wish to include a figure (keep in mind that non-peer-reviewed data will not be posted), please contact the editors directly at firstname.lastname@example.org.