The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs
The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs
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DOI：
10.1016/j.ejphar.2011.01.058
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发表时间：
2011-04-25
影响因子：
5
通讯作者：
Hishinuma, Ieharu
中科院分区：
文献类型：
--
作者：
Kogushi, Motoji;Matsuoka, Toshiyuki;Hishinuma, Ieharu
凝血酶是一种强大的血小板激动剂，其作用由凝血酶受体蛋白酶激活受体 1 (PAR-1) 介导。最近，我们发现 E5555 (1-(3-叔丁基-4-甲氧基-5-吗啉基苯基)-2-(5,6-二乙氧基-7-氟-1-亚氨基-1,3-二氢-2H-异吲哚-2-基)乙酮氢溴酸盐)是一种有效的凝血酶受体拮抗剂。我们评估了 E5555 的抗血小板和抗血栓形成作用。 E5555 抑制高亲和力凝血酶受体激活肽 ([H-3]haTRAP) 与 PAR-1 的结合，半数抑制浓度 (IC50) 值为 0.019 μM。 E5555 对凝血酶和 TRAP 诱导的人血小板聚集显示出有效的抑制作用，IC50 值分别为 0.064 和 0.0311 μM，但没有效果。 ADP 或胶原诱导的血小板聚集。类似地，E5555对凝血酶和TRAP诱导的豚鼠血小板聚集显示出有效和选择性的抑制作用，IC50值分别为0.13和0.097μM。使用豚鼠在光化学诱导血栓形成 (PIT) 模型中评估了 E5555 的体内抗血栓活性。与对照组相比，口服 30 和 100 mg/kg 的 E5555 使闭塞时间分别延长 1.8 倍和 2.4 倍。此外，在最高测试剂量 1000 mg/kg 下，E5555 并未延长豚鼠的出血时间。评估了 E5555 和组织纤溶酶原激活剂 (tPA) 之间的药物相互作用。静脉注射 1 mg/kg tPA 显着延长出血时间，并且口服联合给药 300 mg/kg E5555 不会改变其效果。这些结果表明 E5555 可能成为动脉粥样硬化血栓性疾病的治疗选择。 (C) 2011 Elsevier B.V. 保留所有权利。
Thrombin is a powerful agonist for platelets, the action of which is mediated by the thrombin receptor protease-activated receptor-1 (PAR-1). Recently, we discovered that E5555 (1-(3-tert-butyl-4-methoxy-5-morpholinophenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-2H-isoindol-2-yl) ethanone hydrobromide) is a potent thrombin receptor antagonist. We evaluated the anti-platelet and anti-thrombotic effects of E5555. E5555 inhibited the binding of a high-affinity thrombin receptor-activating peptide ([H-3]haTRAP) to PAR-1 with a half maximal inhibitory concentration (IC50) value of 0.019 mu M. E5555 showed potent inhibitory effects on human platelet aggregation induced by thrombin and TRAP with IC50 values of 0.064 and 0.0311 mu M, respectively, but had no effect on platelet aggregation induced by either ADP or collagen. Similarly, E5555 showed potent and selective inhibitory effects on guinea pig platelet aggregation induced by thrombin and TRAP with IC50 values of 0.13 and 0.097 mu M, respectively. The antithrombotic activity of E5555 in vivo was evaluated in a photochemically-induced thrombosis (PIT) model using guinea pigs. Oral administration of E5555 at 30 and 100 mg/kg prolonged the time to occlusion by 1.8-fold and 2.4-fold, respectively, compared with controls. Furthermore, E5555 did not prolong bleeding time in guinea pigs at the highest tested dosage of 1000 mg/kg. The drug interactions between E5555 and tissue plasminogen activator (tPA) were evaluated. Intravenous administration of 1 mg/kg tPA significantly prolonged bleeding time, and its effects were not altered by the oral co-administration of 300 mg/kg E5555. These results suggest that E5555 could be a therapeutic option for atherothrombotic disease. (C) 2011 Elsevier B.V. All rights reserved.