Discovery of a competitive apelin receptor (APJ) antagonist

ChemMedChem. 2011 Jun 6;6(6):1017-23. doi: 10.1002/cmdc.201100069. Epub 2011 May 10.


The apelin receptor (APJ) is a class A G-protein-coupled receptor (GPCR) and is a putative target for the treatment of cardiovascular and metabolic diseases. Apelin-13 (NH₂-QRPRLSHKGPMPF-COOH) is a vasoactive peptide and one of the most potent endogenous inotropic agents identified to date. We report the design and discovery of a novel APJ antagonist. By using a bivalent ligand approach, we have designed compounds with two 'affinity' motifs and a short series of linker groups with different conformational and non-bonded interaction properties. One of these, cyclo(1-6)CRPRLC-KH-cyclo(9-14)CRPRLC is a competitive antagonist at APJ. Radioligand binding in CHO cells transfected with human APJ gave a K(i) value of 82 nM, competition binding in human left ventricle gave a K(D) value of 3.2 μM, and cAMP accumulation assays in CHO-K1-APJ cells gave a K(D) value of 1.32 μM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apelin Receptors
  • Binding, Competitive
  • CHO Cells
  • Cardiovascular Diseases / drug therapy
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / metabolism
  • Heart Ventricles / metabolism
  • Humans
  • Ligands
  • Metabolic Diseases / drug therapy
  • Models, Molecular
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Protein Binding
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism


  • APLNR protein, human
  • Apelin Receptors
  • Ligands
  • Peptides
  • Receptors, G-Protein-Coupled
  • Cyclic AMP