Pyrimidine Ribonucleotides with Enhanced Selectivity as P2Y6 Receptor Agonists: Novel 4-Alkyloxyimino, (S)-Methanocarba, and 5′-Triphosphate γ-Ester Modifications

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• 作者：Hiroshi Maruoka ; Matthew O. Barrett ; Hyojin Ko ; Dilip K. Tosh ; Artem Melman ; Lauren E. Burianek ; Ramachandran Balasubramanian ; Barkin Berk ; Stefano Costanzi ; T. Kendall Harden ; Kenneth A. Jacobson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：June 10, 2010
• 年：2010
• 卷：53
• 期：11
• 页码：4488-4501
• 全文大小：1097K
• 年卷期：v.53,no.11(June 10, 2010)
• ISSN：1520-4804

文摘

The P2Y₆ receptor is a cytoprotective G-protein-coupled receptor (GPCR) activated by UDP (EC₅₀ = 0.30 μM). We compared and combined modifications to enhance P2Y₆ receptor agonist selectivity, including ribose ring constraint, 5-iodo and 4-alkyloxyimino modifications, and phosphate modifications such as α,β-methylene and extension of the terminal phosphate group into γ-esters of UTP analogues. The conformationally constrained (S)-methanocarba-UDP is a full agonist (EC₅₀ = 0.042 μM). 4-Methoxyimino modification of pyrimidine enhanced P2Y₆, preserved P2Y₂ and P2Y₄, and abolished P2Y₁₄ receptor potency, in the appropriate nucleotide. N⁴-Benzyloxy-CDP (15, MRS2964) and N⁴-methoxy-Cp₃U (23, MRS2957) were potent, selective P2Y₆ receptor agonists (EC₅₀ of 0.026 and 0.012 μM, respectively). A hydrophobic binding region near the nucleobase was explored with receptor modeling and docking. UTP-γ-aryl and cycloalkyl phosphoesters displayed only intermediate P2Y₆ receptor potency but had enhanced stability in acid and cell membranes. UTP-glucose was inactive, but its (S)-methanocarba analogue and N⁴-methoxycytidine 5′-triphospho-γ-[1]glucose were active (EC₅₀ of 2.47 and 0.18 μM, respectively). Thus, the potency, selectivity, and stability of pyrimidine nucleotides as P2Y₆ receptor agonists may be enhanced by modest structural changes.