Ahn Ho-Sam, Chackalamannil Samuel, Boykow George, Graziano Michael P, Foster Carolyn
Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Curr Pharm Des. 2003;9(28):2349-65. doi: 10.2174/1381612033453884.
Thrombin, a plasma serine protease, plays a key role not only in coagulation and hemostasis but in thrombosis, restenosis and atherosclerosis. Thrombin activates platelets, endothelium, inflammatory cells and smooth muscle cells. The cellular action of thrombin is mediated by specific G-protein coupled thrombin receptors called proteinase-activated receptors (protease-activated receptor or PARs). Among the three thrombin receptors, PAR1 is the primary thrombin receptor in human and animal cells with an exception of non-primate platelets. An increased thrombin generation and PAR1 expression are observed on cells within atherosclerotic plaque and thrombus and following vascular injury. Animal studies with PAR1 deficient mice and small molecule antagonists indicate an important role of PAR1 in thrombosis and restenosis and thus the therapeutic potential of a PAR1 antagonist in treating these diseases. Development of a thrombin receptor tethered ligand analog binding assay led to the discovery of several different series of potent, nonpeptide small molecular antagonists of PAR1. These antagonists are PAR1 selective and inhibit most of the cellular effects of thrombin. A PAR1 antagonist has an advantage over a direct thrombin inhibitor since it does not inhibit enzymatic action of thrombin in the coagulation cascade with the consequent minimal bleeding side-effects, unlike a direct thrombin inhibitor. In addition, the emerging evidence for the role of PAR1 in various inflammatory diseases suggests as yet unexplored therapeutic potentials of PAR1 antagonists in various inflammatory diseases.
凝血酶是一种血浆丝氨酸蛋白酶，不仅在凝血和止血过程中起关键作用，还在血栓形成、再狭窄和动脉粥样硬化中发挥作用。凝血酶可激活血小板、内皮细胞、炎症细胞和平滑肌细胞。凝血酶的细胞作用是由特定的G蛋白偶联凝血酶受体介导的，这些受体称为蛋白酶激活受体（protease-activated receptor或PARs）。在三种凝血酶受体中，PAR1是人和动物细胞（非灵长类血小板除外）中的主要凝血酶受体。在动脉粥样硬化斑块和血栓内的细胞以及血管损伤后，可观察到凝血酶生成增加和PAR1表达增加。对PAR1缺陷小鼠和小分子拮抗剂的动物研究表明，PAR1在血栓形成和再狭窄中起重要作用，因此PAR1拮抗剂在治疗这些疾病方面具有治疗潜力。凝血酶受体拴系配体类似物结合测定法的开发导致发现了几种不同系列的PAR1强效非肽小分子拮抗剂。这些拮抗剂具有PAR1选择性，可抑制凝血酶的大多数细胞效应。与直接凝血酶抑制剂不同，PAR1拮抗剂具有优于直接凝血酶抑制剂的优势，因为它不会抑制凝血级联反应中凝血酶的酶促作用，从而使出血副作用最小。此外，PAR1在各种炎症性疾病中作用的新证据表明，PAR1拮抗剂在各种炎症性疾病中具有尚未被探索的治疗潜力。
