Synthesis and potency of novel uracil nucleotides and derivatives as P2Y₂ and P2Y₆ receptor agonists

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• 作者：Hyojin Ko ; Rhonda L. Carter ; Liesbet Cosyn ; Riccardo Petrelli ; Sonia de Castro ; Pedro Besada ; Yixing Zhou ; Loredana Cappellacci ; Palmarisa Franchetti ; Mario Grifantini ; Serge Van Calenbergh ; T. Kendal
• 关键词：Uracil nucleotide ; G protein-coupled receptor ; Phospholipase C ; UDP ; UTP ; Dinucleotide ; Structure– ; activity relationships
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：15 June 2008
• 年：2008
• 卷：16
• 期：12
• 页码：6319-6332
• 全文大小：441 K

文摘

The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y₂, P2Y₄, and P2Y₆ receptors. The 2-thio modification, found previously to enhance P2Y₂ receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y₂ receptor, in the form of Up₄-sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, ,β-methylene-UDP, a P2Y₆ receptor agonist; 30, Up₄-phenyl ester and 34, Up₄-[1]glucose, selective P2Y₂ receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y₂ receptor agonists; 43, the 2-thio analogue of INS37217 (P¹-(uridine-5′)-P⁴-(2′-deoxycytidine-5′)tetraphosphate), a potent and selective P2Y₂ receptor agonist.