Advances in nucleotide-based P2Y₁ antagonism: implications for cardiovascular therapeutics.

Cardiovascular diseases (CVDs) remain a leading cause of global mortality, emphasizing the need for novel, mechanism-driven therapeutics. The P2Y₁ receptor (P2Y₁R), a G protein-coupled purinergic receptor activated by extracellular nucleotides, has emerged as a key regulator of cardiovascular function and dysfunction. Upon activation, P2Y₁R triggers phospholipase C (PLC)-dependent signaling, modulating platelet activation, vascular tone, endothelial integrity, and fibrotic remodeling. Dysregulated P2Y₁R signaling is implicated in thrombosis, atherosclerosis, hypertension, and abnormal platelet reactivity, highlighting its therapeutic potential. Nucleotide bisphosphate antagonists have played a pivotal role in elucidating P2Y₁R pharmacology and guiding drug discovery. The first-generation antagonist MRS2179 demonstrated proof-of-concept for competitive inhibition, but was limited by low potency and metabolic instability. Structural optimization led to MRS2279, exhibiting improved receptor affinity and enzymatic stability. Further refinement produced MRS2500, a highly potent and selective antagonist with nanomolar activity and robust in vivo antithrombotic efficacy without compromising hemostasis. This review integrates advances in P2Y₁R signaling, pharmacology, and structure-based design, emphasizing the evolution of nucleotide antagonists and their translational potential. These insights establish P2Y₁R antagonism as a promising strategy for next-generation cardiovascular therapeutics.