Drug-like Antagonists of P2Y Receptor Subtypes: An Update

The hunt for drug-like P2YR antagonists continues, stimulated by ever-increasing pharmacological evidence for their clinical benefit and the astonishing array of biological functions which they orchestrate, including platelet aggregation, cancer proliferation, pain, neurodegenerative diseases, and immune regulation. Extensive research has identified modulators of P2Y receptors. However, only a limited number of small-molecule antagonists for the P2Y12 receptor have received approval for their clinical use. Recent pioneering discoveries of small-molecule ligand-bound X-ray crystal structures for the P2Y1 and P2Y12 receptors and homology modeling has stimulated research groups to explore orthosteric and allosteric receptor antagonists, aided in part by the discovery of fluorescent P2YR imaging tools and sensitive screening methods that allow the identification of low affinity P2Y receptor antagonists. This Perspective critically assesses P2Y receptor antagonists published since 2016, highlighting potential oral lead- or drug-like compounds that offer opportunities for the development of molecules for clinical evaluation.