Discovery and SAR of aryl hydroxy pyrimidinones as potent small molecule agonists of the GPCR APJ

Bioorg Med Chem Lett. 2020 Apr 1;30(7):126955. doi: 10.1016/j.bmcl.2020.126955. Epub 2020 Jan 22.

Abstract

This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.

Keywords: APJ; Agonist; Atropisomer; GPCR; Heart failure.

MeSH terms

  • Apelin Receptors / agonists*
  • Drug Discovery
  • HEK293 Cells
  • High-Throughput Screening Assays
  • Humans
  • Molecular Structure
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / pharmacology*
  • Structure-Activity Relationship

Substances

  • APLNR protein, human
  • Apelin Receptors
  • Pyrimidinones