凝血酶受体拮抗剂在抗血栓方面的研究进展

20世纪90年代初克隆和发现的凝血酶受体(PAR-1)为研制抗血栓药物提供了一个新靶点,引起学术界和制药业的广泛关注。由于凝血酶受体的特殊活化机制,其自身相连的活化氮端与活化中心近在咫尺,只有结合力很高的小分子化合物才能有效地拮抗凝血酶受体。因此,多年来,只有少数化合物被发现具有较好的凝血酶受体拮抗活性,其中vorapaxar和atopaxar进入了临床试验。vorapaxar在Ⅲ期临床试验发现有显著疗效,但也有出血不良反应,尤其不适用于有中风史的患者。最近,vorapaxar与PAR-1结合的晶体结构已经发表。这些结果为设计和研制新一代凝血酶受体拮抗剂指出了优化的方向,提供了分子水平的结构信息。本文从药物化学角度综述近年来凝血酶受体拮抗剂的研究进展和现状,重点描述vorapaxar、atopaxar以及相关化合物和最新发表的PAR-1拮抗剂。

Recent development in thrombin receptor antagonists as antithrombotics

The thrombin receptor（ protease activated receptor-1, or PAR-1 ）cloned and discovered in the ＇90s provided a new target for antithrombotic drug discovery and development and has received wide attentions in both academic and pharmaceutical research groups. Because of PAR-1 ＇s unique mechanism of activation and its intramolecular activating N-terminal is close to the active site, only small molecules with high affinity can block the receptor effectively. Therefore, only a handful of compounds were discovered over the years to be promising thrombin receptor antagonists. Of these, vorapaxar and atopaxar have entered clinical trials. The phase Ⅲ results from vorapaxar have demonstrated its statistically significant therapeutic benefit although at the same time also revealed its bleeding side effects, especially for patients with a stroke history. Recently, the crystal structure of vorapaxar binding to PAR-1 was published. These results provided future directions of improvements and molecular structural information for the design and discovery of new generation of throm- bin receptor antagonists. This review describes recent developments and current status of thrombin receptor antagonist research from a medicinal chemistry perspective with emphasis on vorapaxar, atopaxar, their related compounds, and most recently published PAR-1 antagonists.