Design and preparation of N-linked hydroxypyridine-based APJ agonists.

Agonism of the apelin receptor (APJ) has demonstrated beneficial effects in models of heart failure. We have previously disclosed compounds such as 4, which showed good APJ agonist activity but were metabolized to the mono-demethylated, non-interconverting atropisomer metabolites. Herein, we detail the design and optimization of a novel series of N-linked APJ agonists with good potency, metabolic stability, and rat pharmacokinetic profile, which are unable to undergo the same metabolic mono-demethylation cleavage.

Identification of a Hydroxypyrimidinone Compound () as a Potent APJ Receptor Agonist for the Potential Treatment of Heart Failure.

This paper describes our continued efforts in the area of small-molecule apelin receptor agonists. Recently disclosed compound showed an acceptable metabolic stability but demonstrated monodemethylation of the dimethoxyphenyl group to generate atropisomer metabolites . In this article, we extended the structure-activity relationship at the C2 position that led to the identification of potent pyrazole analogues with excellent metabolic stability.

Identification of 6-Hydroxypyrimidin-4(1)-one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists.

The apelin receptor (APJ) is a significant regulator of cardiovascular function and is involved in heart failure and other cardiovascular diseases. (Pyr)apelin-13 is one of the endogenous agonists of the APJ receptor. Administration of (Pyr)apelin-13 increases cardiac output in preclinical models and humans.

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]apelin-13, the endogenous ligand for the APJ receptor, improves cardiac function. However, the short half-life of [Pyr]apelin-13 and the need for intravenous administration have limited the therapeutic potential for chronic use.

Discovery of a Hydroxypyridinone APJ Receptor Agonist as a Clinical Candidate.

Apelin-13 is an endogenous peptidic agonist of the apelin receptor (APJ) receptor with the potential for improving cardiac function in heart failure patients. However, the low plasma stability of apelin-13 necessitates continuous intravenous infusion for therapeutic use. There are several approaches to increase the stability of apelin-13 including attachment of pharmacokinetic enhancing groups, stabilized peptides, and Fc-fusion approaches.