Identification of 6-hydroxy-5-phenyl sulfonylpyrimidin-4(1H)-one APJ receptor agonists

Heart failure (HF) treatment remains a critical unmet medical need. Studies in normal healthy volunteers and HF patients have shown that [Pyr(1)]apelin-13, the endogenous ligand for the APJ receptor, improves cardiac func-tion. However, the short half-life of [Pyr(1)]apelin-13 and the need for intravenous administration have limited the therapeutic potential for chronic use. We sought to identify potent, small-molecule APJ agonists with improved pharmaceutical properties to enable oral dosing in clinical studies. In this manuscript, we describe the identification of a series of pyrimidinone sulfones as a structurally differentiated series to the clinical lead (compound 1). Optimization of the sulfone series for potency, metabolic stability and oral bioavailability led to the identification of compound 22, which showed comparable APJ potency to [Pyr(1)]apelin-13 and exhibited an acceptable pharmacokinetic profile to advance to the acute hemodynamic rat model.

Automated summary

The study aims to identify small molecule APJ agonists to improve heart failure treatment. After optimization, a compound with comparable APJ potency to [Pyr(1)]apelin-13, suitable for oral dosing, and acceptable for use in acute hemodynamic rat model was found.