31528-53-7Relevant articles and documents
New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors
Yanachkov, Ivan B.,Chang, Hung,Yanachkova, Milka I.,Dix, Edward J.,Berny-Lang, Michelle A.,Gremmel, Thomas,Michelson, Alan D.,Wright, George E.,Frelinger, Andrew L.
supporting information, p. 204 - 218 (2015/11/24)
Currently approved platelet adenosine diphosphate (ADP) receptor antagonists target only the platelet P2Y12 receptor. Moreover, especially in patients with acute coronary syndromes, there is a strong need for rapidly acting and reversible antiplatelet agents in order to minimize the risk of thrombotic events and bleeding complications. In this study, a series of new P1,P4-di(adenosine-5′) tetraphosphate (Ap4A) derivatives with modifications in the base and in the tetraphosphate chain were synthesized and evaluated with respect to their effects on platelet aggregation and function of the platelet P2Y1, P2Y12, and P2X1 receptors. The resulting structure-activity relationships were used to design Ap4A analogs which inhibit human platelet aggregation by simultaneously antagonizing both P2Y1 and P2Y12 platelet receptors. Unlike Ap4A, the analogs do not activate platelet P2X1 receptors. Furthermore, the new compounds exhibit fast onset and offset of action and are significantly more stable than Ap4A to degradation in plasma, thus presenting a new promising class of antiplatelet agents.
Antagonists of the platelet P(2t) receptor: A novel approach to antithrombotic therapy
Ingall, Anthony H.,Dixon, John,Bailey, Andrew,Coombs, Mandy E.,Cox, David,McInally, Judith I.,Hunt, Simon F.,Kindon, Nicholas D.,Teobald, Barry J.,Willis, Paul A.,Humphries, Robert G.,Leff, Paul,Clegg, Jane A.,Smith, James A.,Tomlinson, Wendy
, p. 213 - 220 (2007/10/03)
The platelet P(2T) receptor plays a major role in platelet aggregation, and its antagonists are predicted to have significant therapeutic potential as antithrombotic agents. We have explored analogues of adenosine triphosphate (ATP), which is a weak, nonselective but competitive P(2T), receptor antagonist. Modification of the polyphosphate side chain to prevent breakdown to the agonist adenosine diphosphate (ADP) and substitution of the adenine moiety to enhance affinity and selectivity for the P(2T) receptor led to the identification of 10e (AR-C67085MX), having an IC50 of 2.5 nM against ADP-induced aggregation of human platelets. Compound 10e was the first very potent antagonist of the P(2T) receptor, with a selectivity for that subtype of the P2 receptor family of > 1000-fold. Further modification of the structure produced compound 101 (AR-C69931MX) having an IC50 of 0.4 nM. In vivo, at maximally effective antithrombotic doses, there is little prolongation of bleeding time (1.4-fold), which is in marked contrast to the 5-6 fold found with GPIIb/IIIa antagonists.
