Biphenyl Acid Derivatives as APJ Receptor Agonists

Area of Science:

• Cardiovascular Pharmacology
• Medicinal Chemistry
• Drug Discovery

Background:

• The apelin peptide (APJ) receptor is a key regulator of cardiovascular function.
• APJ receptor agonists represent a potential therapeutic strategy for heart failure.

Purpose of the Study:

• To discover and optimize novel small molecule agonists targeting the APJ receptor.
• To evaluate the in vitro and in vivo efficacy of identified compounds for potential heart failure treatment.

Main Methods:

• High-throughput screening (HTS) to identify initial lead compounds.
• Structure-activity relationship (SAR) studies for chemical optimization.
• In vitro receptor binding assays and in vivo hemodynamic assessments in rodent models.

Main Results:

• Discovery of biphenyl acid derivatives as potent APJ receptor agonists.
• Lead compound 15a exhibited in vitro potency comparable to endogenous apelin-13.
• Compound 15a demonstrated dose-dependent increases in cardiac output in vivo, with no significant changes in mean arterial blood pressure or heart rate.

Conclusions:

• Biphenyl acid derivatives are effective APJ receptor agonists.
• Compound 15a displays a favorable hemodynamic profile, suggesting therapeutic potential for heart failure.