Discovery of a competitive apelin receptor (APJ) antagonist

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 .