Cardiovascular response to small-molecule APJ activation.

Area of Science:

• Cardiovascular Pharmacology
• Medicinal Chemistry
• Heart Failure Pathophysiology

Background:

• Heart failure (HF) is a significant clinical challenge with limited therapeutic options.
• The apelin receptor (APJ) pathway modulates cardiovascular function and shows therapeutic potential in HF.
• Current apelin-based therapies are limited by short half-lives, necessitating continuous infusion.

Purpose of the Study:

• To discover and develop small-molecule agonists of the apelin receptor (APJ) with improved pharmacokinetic properties.
• To evaluate the efficacy of these novel agonists in preclinical models of heart failure.

Main Methods:

• Medicinal chemistry campaign to identify small-molecule APJ agonists mimicking apelin-13.
• In vivo studies using rat and canine models of cardiac dysfunction and myocardial infarction.
• Assessment of cardiac function, systemic vascular resistance, and myocardial collagen content.

Main Results:

• Discovery of potent small-molecule APJ agonists with efficacy comparable to apelin.
• Acute administration improved systolic function and reduced vascular resistance in rat HF models.
• Chronic oral dosing in a rat myocardial infarction model improved diastolic function and reduced fibrosis, similar to losartan.

Conclusions:

• Small-molecule APJ agonists represent a feasible and potentially viable oral therapeutic strategy for HF.
• These agonists demonstrate favorable drug-like properties compared to endogenous apelin.
• Potential limitations for APJ agonism in HF treatment, such as lack of additivity with standard therapies, were identified.