Reversible, orally available ADP receptor (P2Y₁₂) antagonists Part I: Hit to lead process.

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• The ADP receptor P2Y12 is a key target for antiplatelet therapies.
• Development of orally available, reversible antagonists is crucial for cardiovascular disease management.

Purpose of the Study:

• To describe the hit-to-lead process for identifying novel, orally available P2Y12 antagonists.
• To optimize initial screening hits into potential drug candidates with favorable pharmacokinetic properties.

Main Methods:

• High-throughput screening (HTS) to identify initial hit compounds.
• Parallel synthesis and Structure-Activity Relationship (SAR) studies for lead optimization.
• In vitro assays for metabolic stability (liver microsomes) and receptor antagonism (ADP-induced platelet aggregation).

Main Results:

• Identified lead compounds 22 and 23 through systematic optimization.
• Compound 23 demonstrated potent, reversible P2Y12 antagonism (K_B = 94 nM).
• Compounds exhibited high metabolic stability and oral absorption in preclinical models.

Conclusions:

• The described hit-to-lead process successfully generated promising P2Y12 antagonist lead compounds.
• Compound 23 represents a viable starting point for extensive lead optimization due to its potency and pharmacokinetic profile.
• Further development of this structural class holds potential for new antiplatelet agents.