The P2Y 12 receptor as a therapeutic target in cardiovascular disease
The P2Y 12 receptor as a therapeutic target in cardiovascular disease
复制标题
DOI：
10.1080/09537100120058739
复制
发表时间：
2001-01
期刊：
影响因子：
3.3
通讯作者：
R. Storey
中科院分区：
文献类型：
--
作者：
R. Storey
冠状动脉血栓形成合并动脉粥样硬化斑块破裂是急性冠状动脉综合征的主要原因，血小板在血栓形成中起着至关重要的作用。虽然阿司匹林已成功地降低心血管疾病的发病率和死亡率，但其有限的抗血小板作用的认识刺激了对更有效的抗血小板药物的研究。噻吩并吡啶类、噻氯匹定和氯吡格雷通过代谢物作用于血小板ADP受体亚型，现在称为P2 Y12（以前称为P2 T、P2 T AC、P2 Y ADP或P2 Y cyc），这些药物已证实具有临床疗效。已经开发了天然P2 Y12受体拮抗剂ATP的类似物，其直接作用于受体并具有快速起效。一种这样的拮抗剂AR-C69931 MX正在开发用于临床使用。AR-C69931 MX是ADP诱导的血小板活化、聚集和分泌的有效拮抗剂，并且鉴于P2 Y12受体在放大血小板应答中的中心作用，还拮抗由所有其他激动剂诱导的血小板应答，包括促凝血活性。静脉注射AR-C69931 MX治疗急性冠脉综合征患者的II期研究表明，该药物起效迅速，迅速达到稳态抑制血小板聚集，半衰期仅为几分钟。AR-C69931 MX在这些患者中作为连续治疗似乎是安全和耐受性良好的，并且比氯吡格雷更有效地抑制血小板功能。口服活性ATP类似物也正在开发中，可能比氯吡格雷更有效。血小板糖蛋白IIb/IIIa拮抗剂的局限性为开发替代抗血小板药物留下了空间。
Coronary thrombosis complicating rupture of atherosclerotic plaque is the predominant cause of acute coronary syndromes and platelets play a crucial role in this thrombus formation. Whilst aspirin has been successful in reducing cardiovascular morbidity and mortality, appreciation of its limited antiplatelet effects has stimulated the search for more effective antiplatelet agents. The thienopyridines, ticlopidine and clopidogrel, act, via metabolites, on the platelet ADP receptor subtype now designated P2Y 12 (formerly P 2T , P2T AC , P2Y ADP or P2Y cyc ) and these agents have proven clinical efficacy. Analogues of the natural P2Y 12 receptor antagonist ATP have been developed that act directly on the receptor and have a rapid onset of action. One such antagonist, AR-C69931MX, is being developed for clinical use. AR-C69931MX is a potent antagonist of ADPinduced platelet activation, aggregation and secretion and also antagonises platelet responses, including procoagulant activity, induced by all other agonists in view of the central role of the P2Y 12 receptor in amplifying platelet responses. Phase II studies of intravenous AR-C69931MX in patients with acute coronary syndromes show that this agent has a rapid onset of action, rapidly achieving steady-state inhibition of platelet aggregation, with a half-life of only a few minutes. AR-C69931MX appears to be safe and well tolerated as adjunctive therapy in these patients, and more effective inhibition of platelet function is achieved than with clopidogrel. Orally active ATP analogues are also being developed that may be more effective than clopidogrel. Limitations of platelet glycoprotein IIb/IIIa antagonists leave scope for development of alternative antiplatelet agents.