TY - JOUR
T1 - Identification of hydrolytically stable and selective P2Y1 receptor agonists
AU - Eliahu, Shay E.
AU - Camden, Jean
AU - Lecka, Joanna
AU - Weisman, Gary A.
AU - Sévigny, Jean
AU - Gélinas, Sylvie
AU - Fischer, Bilha
PY - 2009/4
Y1 - 2009/4
N2 - 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.
AB - 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.
KW - NPP
KW - NTPDase
KW - Nucleotides
KW - P2Y receptor
UR - http://www.scopus.com/inward/record.url?scp=61349140591&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2008.07.015
DO - 10.1016/j.ejmech.2008.07.015
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C2 - 18760862
AN - SCOPUS:61349140591
SN - 0223-5234
VL - 44
SP - 1525
EP - 1536
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
IS - 4
ER -