biostudies-literatureUnknown5(8)Ason BHeart 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 obtaiJCI insight132898https://www.ebi.ac.uk/biostudies/studies/S-EPMC7205427biostudies-literatureCardiovascular response to small-molecule APJ activation.PMC7205427Gao BMa XMihardja SGuo QWang JSwaminath GFielden MBoden AHouze JVargas HMKhakoo AYChen YQu YChen RHoagland KMWong JAson BSutherland WChintalgattu VTurk JRHu LADransfield PChan JVeniant MMNguyen KSun YLi NRajamani SLi XChui RWZhang YMa JPattaropong VLiu DfalseCardiovascular response to small-molecule APJ activation.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 obtai2020-01-01T00:00:00Z2020 Apr2026-05-03T05:26:29.696Z2025-04-05T15:28:29.009ZS-EPMC72054273220838410.1172/jci.insight.132898