New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors.
New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors.
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DOI：
10.1016/j.ejmech.2015.10.055
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发表时间：
2016-01-01
影响因子：
6.7
通讯作者：
Frelinger AL 3rd
中科院分区：
文献类型：
--
作者：
Yanachkov IB;Chang H;Yanachkova MI;Dix EJ;Berny-Lang MA;Gremmel T;Michelson AD;Wright GE;Frelinger AL 3rd
目前批准的血小板二磷酸腺苷（ADP）受体拮抗剂仅靶向血小板P2 Y12受体。此外，特别是在急性冠状动脉综合征患者中，迫切需要快速作用和可逆的抗血小板药物，以最大限度地降低血栓形成事件和出血并发症的风险。本研究合成了一系列新的P1，P4-二（腺苷-5 ′）四磷酸（Ap 4A）衍生物，并对其碱基和四磷酸链进行了修饰，评价了它们对血小板聚集和血小板P2 Y1、P2 Y12和P2 X1受体功能的影响。所得到的结构-活性关系被用于设计通过同时拮抗P2 Y1和P2 Y12血小板受体来抑制人血小板聚集的Ap 4A类似物。与Ap 4A不同，这些类似物不激活血小板P2 X1受体。此外，新化合物表现出快速的起效和抵消作用，并且在血浆中的降解比Ap 4A显著更稳定，因此呈现出一类新的有希望的抗血小板剂。
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.