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[摘要]：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-beta,gamma-CH2 analogues 2-4, and evaluated their chemical and metabolic stabilities and activities at P2Y(1,2,4,6) receptors. Analogues 2-4 exhibited t(1/2) values of 14.5-65 h in gastric juice pH. They were completely resistant to alkaline phosphatase for 30 min at 37 degrees C and slowly hydrolyzed in human blood serum (t(1/2) 12.7-71.9 h). In comparison to ATP, analogues 2-4 were barely hydrolyzed by nucleoside triphosphate diphosphohydrolases, NTPDase 1,2,3,8 (<8% hydrolysis), and nucleotide pyrophosphatases, NPP1,3 (<= 10% hydrolysis). Analogues 2 and 4B were selective agonists of the P2Y(1)R with EC50S of 0.08 and 17.2 mu M, respectively. These features make analogues 2 and 4B potential therapeutic agents for health disorders involving the P2Y(1)R. (C) 2008 Elsevier Masson SAS. All rights reserved. |
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