Blockade of protease-activated receptor-4 (PAR4) provides robust antithrombotic activity with low bleeding
Blockade of protease-activated receptor-4 (PAR4) provides robust antithrombotic activity with low bleeding
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DOI：
10.1126/scitranslmed.aaf5294
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发表时间：
2017-01-04
影响因子：
17.1
通讯作者：
Yang, Jing
中科院分区：
文献类型：
--
作者：
Wong, Pancras C.;Seiffert, Dietmar;Yang, Jing
抗血小板药物已被证明是治疗心脑血管疾病的有效药物。然而，现有的药物受到不必要的、有时甚至危及生命的出血的影响，限制了药物的使用或剂量。对于一种具有强大疗效和低出血风险的抗血小板药物，医学上仍有大量未得到满足的需求。凝血酶是一种有效的血小板激动剂，通过G蛋白(异源三聚体鸟嘌呤核苷酸结合蛋白)偶联的蛋白酶激活受体PAR1和PAR4直接诱导血小板激活。PAR1拮抗剂被批准用于临床，但其使用受到大量出血风险的限制。相反，PAR4作为抗血小板靶点的潜力还没有得到很好的表征。使用抗PAR4抗体，我们证明了在豚鼠中使用PAR4抑制具有低出血风险和有效的抗血栓形成特征。随后，高通量筛选和广泛的药物化学努力导致了BMS-986120的发现，它是一种口服活性的、选择性的和可逆的PAR4拮抗剂。在食蟹猴动脉血栓形成模型中，BMS-986120显示出强大而高效的抗血栓活性。与在相同的非人类灵长类动物模型中测试的标准抗血小板药物氯吡格雷相比，BMS-986120还显示出较低的出血易感性和明显更宽的治疗窗口。这些临床前研究结果明确了PAR4在调节血小板聚集中的生物学作用。此外，他们指出，靶向PAR4是一种有吸引力的抗血小板策略，与目前的治疗标准相比，有可能以更高的安全性治疗动脉粥样硬化血栓形成的高危患者。
Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs are compromised by unwanted and sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need for an antiplatelet drug with strong efficacy and low bleeding risk. Thrombin is a potent platelet agonist that directly induces platelet activation via the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled protease-activated receptors PAR1 and PAR4. A PAR1 antagonist is approved for clinical use, but its use is limited by a substantial bleeding risk. Conversely, the potential of PAR4 as an antiplatelet target has not been well characterized. Using anti-PAR4 antibodies, we demonstrated a low bleeding risk and an effective antithrombotic profile with PAR4 inhibition in guinea pigs. Subsequently, high-throughput screening and an extensive medicinal chemistry effort resulted in the discovery of BMS-986120, an orally active, selective, and reversible PAR4 antagonist. In a cynomolgus monkey arterial thrombosis model, BMS-986120 demonstrated potent and highly efficacious antithrombotic activity. BMS-986120 also exhibited a low bleeding liability and a markedly wider therapeutic window compared to the standard antiplatelet agent clopidogrel tested in the same nonhuman primate model. These preclinical findings define the biological role of PAR4 in mediating platelet aggregation. In addition, they indicate that targeting PAR4 is an attractive antiplatelet strategy with the potential to treat patients at a high risk of atherothrombosis with superior safety compared with the current standard of care.