Leonardi Sergio, Tricoci Pierluigi, Becker Richard C
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
Adv Cardiol. 2012;47:87-99. doi: 10.1159/000338045. Epub 2012 Aug 9.
The unifying basis of acute coronary syndrome (ACS) is the complication of a vulnerable coronary plaque, an event primarily mediated by platelet activation. Three major pathways are predominantly involved in this process: thromboxane A(2) via the thromboxane A(2) receptor, adenosine diphosphate via the P2Y(12) receptor, and thrombin via the protease-activated receptor (PAR)-1, with the latter being the most potent platelet activator. Despite the effective inhibition of the first two pathways with aspirin and an expanding family of P2Y(12) inhibitors, respectively, the recurrence of ischemic events in patients with ACS remains high. There is also a growing concern regarding the safety profile in terms of bleeding with more powerful antiplatelet agents, which has tempered expectations of newly developed compounds. PAR-1 inhibitors are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preliminary data indicate that these compounds have the potential to improve ischemic prognosis without increasing the bleeding risk. In this chapter we will discuss the rationale for developing this novel class of antiplatelet agents and specifically, the two compounds in most advanced clinical development, vorapaxar and atopaxar.
急性冠状动脉综合征（ACS）的统一基础是易损冠状动脉斑块的并发症，这一事件主要由血小板活化介导。该过程主要涉及三条主要途径：通过血栓素A2受体的血栓素A2、通过P2Y12受体的二磷酸腺苷以及通过蛋白酶激活受体（PAR）-1的凝血酶，其中后者是最有效的血小板激活剂。尽管分别使用阿司匹林和不断扩大的P2Y12抑制剂家族有效地抑制了前两条途径，但ACS患者缺血事件的复发率仍然很高。人们也越来越关注更强效抗血小板药物在出血方面的安全性，这降低了对新开发化合物的期望。PAR-1抑制剂是一类新型抗血小板药物，可抑制凝血酶介导的血小板活化。初步数据表明，这些化合物有可能改善缺血预后而不增加出血风险。在本章中，我们将讨论开发这类新型抗血小板药物的基本原理，特别是两种处于临床开发最前沿的化合物，vorapaxar和atopaxar。
