Antithrombotic P2Y₁₂ receptor antagonists: recent developments in drug discovery

Area of Science:

• Pharmacology
• Biochemistry
• Medicinal Chemistry

Background:

• The P2Y12 receptor, a G-protein-coupled receptor (GPCR), is crucial in platelet activation and is highly expressed in platelets and the brain.
• P2Y12 receptor antagonists are clinically significant as antithrombotic agents, preventing blood clots.

Purpose of the Study:

• To provide a comprehensive overview of diverse chemical scaffolds developed as P2Y12 receptor antagonists.
• To highlight P2Y12 receptor antagonists that have achieved therapeutic importance.

Main Methods:

• Review of literature on P2Y12 receptor antagonist research and development.
• Classification of antagonists based on their chemical structures and mechanisms of action.

Main Results:

• Identification of multiple distinct chemical scaffolds targeting the P2Y12 receptor.
• Categorization into irreversible thienotetrahydropyridines (prodrugs) and various reversible competitive antagonists.
• Examples of reversible antagonists include adenine nucleotide analogs, piperazinyl-glutamate derivatives (quinolines, pyridines, pyrimidines), and anthraquinone derivatives.

Conclusions:

• Significant progress has been made in developing P2Y12 receptor antagonists with diverse chemical structures.
• Several identified scaffolds have successfully translated into clinically valuable antithrombotic therapeutics.