Identification of hydrolytically stable and selective P2Y1 receptor agonists

Shay E. Eliahu, Jean Camden, Joanna Lecka, Gary A. Weisman, Jean Sévigny, Sylvie Gélinas, Bilha Fischer

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


P2Y nucleotide receptors (P2YRs) are attractive pharmaceutical targets. Most P2YR agonists proposed as drugs consist of a nucleotide scaffold, but their use is limited due to their chemical and enzymatic instabilities. To identify drug candidates, we developed non-hydrolyzable P2YR agonists. We synthesized ATP-β,γ-CH2 analogues 2-4, and evaluated their chemical and metabolic stabilities and activities at P2Y1,2,4,6 receptors. Analogues 2-4 exhibited t1/2 values of 14.5-65 h in gastric juice pH. They were completely resistant to alkaline phosphatase for 30 min at 37 °C and slowly hydrolyzed in human blood serum (t1/2 12.7-71.9 h). In comparison to ATP, analogues 2-4 were barely hydrolyzed by nucleoside triphosphate diphosphohydrolases, NTPDase1,2,3,8 (<8% hydrolysis), and nucleotide pyrophosphatases, NPP1,3 (≤10% hydrolysis). Analogues 2 and 4B were selective agonists of the P2Y1R with EC50s of 0.08 and 17.2 μM, respectively. These features make analogues 2 and 4B potential therapeutic agents for health disorders involving the P2Y1R.

Original languageEnglish
Pages (from-to)1525-1536
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Issue number4
StatePublished - Apr 2009


  • NPP
  • NTPDase
  • Nucleotides
  • P2Y receptor


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