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

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Citation

Ko H, Carter RL, Cosyn L, Petrelli R, de Castro S, Besada P, Zhou Y, Cappellacci L, Franchetti P, Grifantini M, Van Calenbergh S, Harden TK, Jacobson KA

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

Bioorg Med Chem. 2008 Jun 15;16(12):6319-32. doi: 10.1016/j.bmc.2008.05.013. Epub 2008 May 9.

PubMed ID
18514530 [ View in PubMed
]
Abstract

The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y(2), P2Y(4), and P2Y(6) receptors. The 2-thio modification, found previously to enhance P2Y(2) 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 P2Y(2) receptor, in the form of Up(4)-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, alpha,beta-methylene-UDP, a P2Y(6) receptor agonist; 30, Up(4)-phenyl ester and 34, Up(4)-[1]glucose, selective P2Y(2) receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y(2) receptor agonists; 43, the 2-thio analogue of INS37217 (P(1)-(uridine-5')-P(4)-(2'-deoxycytidine-5')tetraphosphate), a potent and selective P2Y(2) receptor agonist.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
DenufosolP2Y purinoceptor 2EC 50 (nM)140N/AN/ADetails