Design of Small-Molecule Active-Site Inhibitors of the S1A Family Proteases as Procoagulant and Anticoagulant Drugs,Journal of Medicinal Chemistry

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Design of Small-Molecule Active-Site Inhibitors of the S1A Family Proteases as Procoagulant and Anticoagulant Drugs
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-11-09 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00772
Peter M. Fischer ₁

Affiliation

Vitamin K antagonists (VKA) have long been the default drugs for anticoagulant management in venous thrombosis. While efficacious, they are difficult to use due to interpatient dose–response variability and the risks of bleeding. The approval of fondaparinux, a heparin-derived factor Xa (fXa) inhibitor, provided validation for the development of direct oral anticoagulants (DOAC), and currently such inhibitors of thrombin and fXa are in clinical use. These agents can be used without regular coagulation monitoring, but the inherent risk of bleeding complications associated with blocking the common coagulation pathway remains. Efforts are now underway to develop DOACs that inhibit components of the intrinsic and extrinsic coagulation cascades upstream of thrombin and fX. Evidence from humans and from transgenic animal models suggests that this strategy may provide a better therapeutic margin between antithrombotic and antihemostatic effects. Here the design of active-site inhibitors of S1A proteases involved in coagulation and fibrinolysis is summarized.

中文翻译：

S1A家族蛋白酶的小分子活性位点抑制剂作为促凝和抗凝药物的设计

长期以来，维生素K拮抗剂（VKA）一直是静脉血栓形成中抗凝治疗的默认药物。虽然有效，但由于患者之间的剂量反应差异和出血风险而难以使用。肝素衍生的Xa因子抑制剂fondaparinux的批准为直接口服抗凝剂（DOAC）的开发提供了验证，目前这类凝血酶和fXa抑制剂正在临床使用。这些药物无需定期进行凝血监测即可使用，但仍存在与阻断常见凝血途径相关的出血并发症的内在风险。现在正在努力开发可抑制凝血酶和fX上游内源性和外源性凝血级联反应组分的DOAC。来自人类和转基因动物模型的证据表明，该策略可能在抗血栓形成和止血作用之间提供更好的治疗余地。这里总结了涉及凝血和纤维蛋白溶解的S1A蛋白酶活性位点抑制剂的设计。

更新日期：2017-11-09

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