Apelin is the endogenous ligand for the G protein-coupled receptor APJ and exerts a key role in regulating cardiovascular functions. We report herein a novel series of macrocyclic analogues of apelin-13 in which the N- and C-terminal residues as well as the macrocycle composition were chemically modified to modulate structure-activity relationships on the APJ receptor. To this end, the binding affinity and the ability to engage G protein-dependent and G protein-independent signalling pathways of the resulting analogues were assessed. In this series, the position and the nature of the C-terminal aromatic residue is a determinant for APJ interaction and β-arrestin recruitment, as previously demonstrated for linear apelin-13 derivatives. We finally discovered compounds 1, 4, 11 and 15, four potent G protein-biased apelin receptor agonists exhibiting affinity in the nanomolar range for APJ. These macrocyclic compounds represent very useful pharmacological tools to explore the therapeutic potential of the apelinergic system.

The apelinergic system emerges as an important regulator of cardiovascular functions via its actions on the heart, vasculature, and kidney. It also possesses additional beneficial properties, via its actions on the pancreas and skeletal muscle, on type 2 diabetes. The apelinergic system distinguishes itself by the presence of two structurally distinct sets of endogenous ligands, the Apelins (–13, −17, and −36) and Elabela, which both activate the apelin (APJ) receptor. In the past decade, numerous peptidic ligands have been used to better understand the structure–activity relationship of apelin (and more recently Elabela), providing important tools to rationalize how ligand modifications impact receptor structure and dynamics as well as its downstream signaling. The recently disclosed structure of the apelin receptor in complex with an analogue of apelin‐17 provides an important tool in this quest. In this review, we first summarize the physiopharmacology of the apelinergic system, then, review existing knowledge on the various ligands of the apelin receptor with an emphasis on peptidic ligands, although small molecules are covered as well. Throughout this work, we tried to integrate existing knowledge of ligands’ pharmacological profiles with structure and signaling profile.