| Summary: | The P2Y2 receptor (P2Y2R) is an exciting therapeutic target for numerous diseases including atherosclerosis, idiopathic pulmonary fibrosis, and cancer. Despite this, there are a limited number of receptor antagonists available, none of which are clinically viable. The highest affinity P2Y2R antagonists detailed are AR-C118925 and its thiazole-based analogues, for which physiochemical properties remain a barrier for future drug development.
The work presented in this project details the design, synthesis, and evaluation of new chemotype P2Y2R antagonists and fluorescent ligands, which provide scope for future drug development projects to depart from ARC118925 and its analogues. The new chemotype P2Y2R antagonists and fluorescent ligands retained micromolar affinity for the receptor, despite the absence of the tricyclic ring system and thiouracil, with the presence of a terminal acidic group on the thiazole substituent being crucial for P2Y2R activity. The fluorescent ligand 4.09 (pKd = 5.24 ± 0.04, n = 5), which appears to bind to the P2Y2R on the intracellular side of the plasma membrane, offers exciting opportunities to target this difficult to drug receptor with new modalities that could overcome existing limitations in developing P2Y2R antagonists.
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