Synthesis and structure-activity relationship of uracil nucleotide derivatives towards the identification of human P2Y₆ receptor antagonists

P2Y₆ receptor (P2Y₆-R) is involved in various physiological and pathophysiological events. With a view to set rules for the design of UDP-based reversible P2Y₆-R antagonists as potential drugs, we established structure-activity relationship of UDP analogues, bearing modifications at the uracil ring, ribose moiety, and the phosphate chain. For instance, C5-phenyl- or 3-NMe-uridine-5′-α,β-methylene-diphosphonate, 16 and 23, or lack of 2′-OH, in 12-15, resulted in loss of both agonist and antagonist activity toward hP2Y₆-R. However, uridylyl phosphosulfate, 19, selectively inhibited hP2Y₆-R (IC₅₀ 112 μM) versus P2Y₂/₄-Rs. In summary, we have established a comprehensive SAR for hP2Y₆-R ligands towards the development of hP2Y₆-R antagonists.