Cardiovascular response to small-molecule APJ activation

  • JCI Insight. 2020 Apr 23;5(8):e132898. doi: 10.1172/jci.insight.132898.
Brandon Ason  1 ,  Yinhong Chen  1 ,  Qi Guo  1 ,  Kimberly M Hoagland  2 ,  Ray W Chui  2 ,  Mark Fielden  2 ,  Weston Sutherland  2 ,  Rhonda Chen  1 ,  Ying Zhang  1 ,  Shirley Mihardja  1 ,  Xiaochuan Ma  3 ,  Xun Li  3 ,  Yaping Sun  3 ,  Dongming Liu  1 ,  Khanh Nguyen  1 ,  Jinghong Wang  1 ,  Ning Li  1 ,  Sridharan Rajamani  1 ,  Yusheng Qu  2 ,  BaoXi Gao  2 ,  Andrea Boden  2 ,  Vishnu Chintalgattu  1 ,  Jim R Turk  2 ,  Joyce Chan  1 ,  Liaoyuan A Hu  3 ,  Paul Dransfield  4 ,  Jonathan Houze  4 ,  Jingman Wong  1 ,  Ji Ma  1 ,  Vatee Pattaropong  4 ,  Murielle M Véniant  2 ,  Hugo M Vargas  2 ,  Gayathri Swaminath  1 ,  Aarif Y Khakoo  1
Affiliations
  • 1. Amgen Research, South San Francisco, California, USA.
  • 2. Amgen Research, Thousand Oaks, California, USA.
  • 3. Amgen Research, Amgen Asia R&D Center, Shanghai, China.
  • 4. Amgen Research, Cambridge, Massachusetts, USA.
PMID: 32208384 DOI: 10.1172/jci.insight.132898
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.

Keywords
Cardiology; Drug therapy; G-protein coupled receptors; Heart failure; Therapeutics.
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