Protease-activated receptors (PARs) are a ubiquitously expressed class of G-protein-coupled receptors (GPCRs) that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs since the 1990s. Vorapaxar and drotrecogin-alfa are approved PAR1-targeted therapeutics, but safety concerns have limited the clinical use of vorapaxar and questions regarding the efficacy of drotrecogin-alfa led to its withdrawal from the market. New understanding of mechanisms of PAR1 function, discovery of improved strategies for modifying PAR1 function, and identification of novel indications for PAR1 modulators have provided new opportunities for therapies targeting PAR1. In this review, we critically evaluate prospects for the next generation of PAR1-targeted therapeutics.

蛋白酶激活受体（PARs）是一类普遍表达的G蛋白偶联受体（GPCR），它使细胞能够以细微而动态的方式对细胞外环境中的蛋白酶作出反应。PAR1是原型家族成员，自1990年代以来一直是大规模药物开发计划的对象。Vorapaxar和drotrecogin-alfa被批准为靶向PAR1的治疗剂，但出于安全性考虑，vororaxar的临床使用受到限制，而有关drotrecogin-alfa功效的疑问导致其退出市场。对PAR1功能机制的新认识，用于修饰PAR1功能的改进策略的发现以及对PAR1调节剂的新适应症的鉴定为靶向PAR1的疗法提供了新的机会。在这篇评论中，