Cardiovascular response to small-molecule APJ activation
- 23 April 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
Abstract
Heart failure (HF) remains a grievous illness with poor prognosis even with optimal care. The apelin receptor (APO counteracts the pressor effect of angiotensin 11, 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 API 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 AP) ligand with more favorable drug-like properties and highlights potential limitations for AP) agonism for this indication.This publication has 81 references indexed in Scilit:
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