Design, synthesis, and biological evaluation of 1H-1,2,4-triazole-3-carboxamides as apelin receptor agonists.

The apelin receptor (AplnR) is a prominent peptide-binding Class A G protein-coupled receptor (GPCR) involved in the regulation of cardiovascular, gastrointestinal, and immune functions, as well as skeletal development. Activation of the AplnR-mediated β-arrestin pathway has been associated with adverse effects including pathological cardiac hypertrophy and heart failure. Therefore, the development of G protein-biased small-molecule agonists is expected to provide an improved safety profile for long-term therapeutic use. In this study, a series of 1H-1,2,4-triazole-3-carboxamide derivatives were designed and synthesized as small-molecule AplnR agonists. Among them, the most promising compound B-007 exhibited potent agonist activity with an EC50 value of 11.6 nM. Notably, compared with an endogenous ligand apelin-13, B-007 demonstrated a pronounced G protein bias with abolished β-arrestin signaling. These results identified a new promising scaffold for the development of G protein-biased agonists.