Damiano Bruce P, Derian Claudia K, Maryanoff Bruce E, Zhang Han-Cheng, Gordon Patricia Andrade
Johnson and Johnson Pharmaceutical Research and Development, Spring House, PA 19477-0776, USA.
Cardiovasc Drug Rev. 2003 Winter;21(4):313-26. doi: 10.1111/j.1527-3466.2003.tb00124.x.
Protease activated receptor-1 (PAR-1) is a key mediator of the cellular actions of alpha-thrombin. Thus, antagonism of this unique G-protein coupled receptor with a small molecule represents a means of selectively inhibiting thrombin's cellular actions without inhibiting its proteolytic activity. RWJ-58259 (alphaS)-N-[(1S)-3-amino-1-[[(phenylmethyl)- amino]carbonyl]propyl]-alpha-[[[[[1-(2,6-dichlorophenyl)methyl]-3-(1-pyrrolidinylmethyl)-1H-indazol-6-yl]amino]carbonyl]amino]-3,4-difluorobenzenepropanamide) is a potent and selective inhibitor of PAR-1 identified as part of a synthetic chemistry program based upon a de novo design approach. RWJ-58259 inhibited thrombin-induced platelet aggregation in human platelets with an IC50 of 0.37 microM without inhibiting thrombin's proteolytic activity or aggregation induced by other agonists. RWJ-58259 was not effective in guinea pig models of thrombosis. This reflected the presence of a second thrombin-sensitive receptor system in guinea pigs (PAR-3/4) and the selectivity of RWJ-58259 for PAR-1. However, RWJ-58259 was effective in a non-human primate model of thrombosis. Because human platelets have a PAR expression profile similar to the non-human primate, PAR-1 antagonism has the potential to be antithrombotic in humans. RWJ-58259 also inhibited thrombin-induced intracellular calcium signaling and proliferation in rat vascular smooth muscle cells. Perivascular application of RWJ-58259 in vivo significantly inhibited arterial injury-induced stenosis in a rat model of balloon angioplasty. These preclinical results suggest a potential clinical utility of RWJ-58259 for treatment of thrombotic disorders and vascular injury associated with acute coronary interventions and atherosclerosis. Given the potential role of PAR-1 in thrombin's actions in other cell types and disease states, RWJ-58259 provides a means for assessing additional clinical utilities of PAR-1 antagonism in disease conditions such as inflammation, cancer and neurodegeneration.
蛋白酶激活受体-1（PAR-1）是α-凝血酶细胞作用的关键介质。因此，用小分子拮抗这种独特的G蛋白偶联受体代表了一种在不抑制凝血酶蛋白水解活性的情况下选择性抑制其细胞作用的方法。RWJ-58259（(αS)-N-[(1S)-3-氨基-1-[[(苄基)氨基]羰基]丙基]-α-[[[[[1-(2,6-二氯苯基)甲基]-3-(1-吡咯烷基甲基)-1H-吲唑-6-基]氨基]羰基]氨基]-3,4-二氟苯丙酰胺）是一种强效且选择性的PAR-1抑制剂，它是基于从头设计方法的合成化学项目的一部分。RWJ-58259抑制人血小板中凝血酶诱导的血小板聚集，IC50为0.37微摩尔，而不抑制凝血酶的蛋白水解活性或其他激动剂诱导的聚集。RWJ-58259在豚鼠血栓形成模型中无效。这反映了豚鼠中存在第二种凝血酶敏感受体系统（PAR-3/4）以及RWJ-58259对PAR-1的选择性。然而，RWJ-58259在非人类灵长类动物血栓形成模型中有效。由于人类血小板具有与非人类灵长类动物相似的PAR表达谱，PAR-1拮抗作用在人类中具有抗血栓形成的潜力。RWJ-58259还抑制凝血酶诱导的大鼠血管平滑肌细胞内钙信号传导和增殖。在体内对RWJ-58259进行血管周围给药可显著抑制大鼠球囊血管成形术模型中动脉损伤诱导的狭窄。这些临床前结果表明RWJ-58259在治疗与急性冠状动脉干预和动脉粥样硬化相关的血栓形成疾病和血管损伤方面具有潜在的临床应用价值。鉴于PAR-1在凝血酶在其他细胞类型和疾病状态中的作用中的潜在作用，RWJ-58259为评估PAR-1拮抗作用在炎症、癌症和神经退行性变等疾病状况中的其他临床应用提供了一种手段。
