Structural modifications of UMP, UDP, and UTP leading to subtype-selective agonists for P2Y2, P2Y4, and P2Y6 receptors

Article abstract of DOI:10.1021/jm1016297

A large series of derivatives and analogues of the uracil nucleotides UMP, UDP, and UTP with modifications in various positions of the uracil moiety and/or the phosphate groups were synthesized and evaluated at human P2Y₂, P2Y₄, and P2Y₆ receptors. 2-(Ar)alkylthio substitution of UMP and UDP was best tolerated by the P2Y₂ receptor. 2-Phenethylthio-UMP (13e) showed an EC₅₀ value of 1.3 μM at P2Y₂ and >70-fold selectivity versus P2Y₄ and P2Y ₆ receptors. Substitution of the 2-keto group in UMP by NH (13g, iso-CMP) resulted in the first potent and selective P2Y₄ agonist (EC₅₀ 4.98 μM, >20-fold selective vs P2Y₂ and P2Y₆). In contrast, replacement of the 2-keto function in UDP by NH yielded a potent P2Y₂ agonist (12g, iso-CDP, EC₅₀ = 0.604 μM, >100-fold selective). In an attempt to obtain metabolically stable UTP analogues, β,γ-dichloro- and β,γ-difluoro-methylene-UTP derivatives were synthesized. The triphosphate modifications were much better tolerated by P2Y₂, and in some cases also by P2Y₆, than by P2Y₄ receptors. 4-Thio-β,γ-difluoromethylene-UTP (14g) was a potent P2Y₂ agonist with an EC₅₀ value of 0.134 μM and >50-fold selectivity. N3-Phenacyl-β,γ-dichloromethylene- UTP (14b) proved to be a potent P2Y₆ receptor agonist (EC ₅₀ 0.142 μM) with high selectivity versus P2Y₄ (50-fold) and moderate selectivity versus P2Y₂ receptors (6-fold).