Structural Modifications of UMP, UDP, and UTP Leading to Subtype-Selective Agonists for P2Y2, P2Y4, and P2Y6 Receptors

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• 作者：Ali El-Tayeb ; Aidong Qi ; Robert A. Nicholas ; Christa E. Mu虉ller
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 28, 2011
• 年：2011
• 卷：54
• 期：8
• 页码：2878-2890
• 全文大小：1133K
• 年卷期：v.54,no.8(April 28, 2011)
• ISSN：1520-4804

文摘

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 渭M at P2Y₂ and >70-fold selectivity versus P2Y₄ and P2Y₆ 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 渭M, >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 渭M, >100-fold selective). In an attempt to obtain metabolically stable UTP analogues, 尾,纬-dichloro- and 尾,纬-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-尾,纬-difluoromethylene-UTP (14g) was a potent P2Y₂ agonist with an EC₅₀ value of 0.134 渭M and >50-fold selectivity. N3-Phenacyl-尾,纬-dichloromethylene-UTP (14b) proved to be a potent P2Y₆ receptor agonist (EC₅₀ 0.142 渭M) with high selectivity versus P2Y₄ (50-fold) and moderate selectivity versus P2Y₂ receptors (6-fold).