Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants
Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants
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DOI：
10.1021/jm060978s
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发表时间：
2006-12-28
影响因子：
7.3
通讯作者：
Strickler, James E.
中科院分区：
文献类型：
--
作者：
Lin, Jian;Deng, Hongfeng;Strickler, James E.
人凝血因子XIa（FXIa）是一种丝氨酸蛋白酶，通过凝血酶、FXIIa或自活化作用对因子XI进行位点特异性切割而活化，是凝血级联放大阶段的关键酶。为了研究FXIa抑制剂作为安全抗凝剂的潜力，设计并合成了一系列FXIa的强效、选择性拟肽抑制剂。这些抑制剂中的一些显示出低纳摩尔FXIa抑制活性，具有> 1000倍FXa选择性和> 100倍凝血酶选择性。这些抑制剂之一36的X射线结构证明了其与FXIa的独特结合相互作用。化合物32在2.4 μ M时使人血浆中活化的部分促凝血酶原激酶时间加倍，并且在静脉血栓形成的大鼠模型中有效。这些数据表明，因子XIa在静脉血栓形成中起着重要作用，可能是一个合适的抗血栓治疗的发展目标。
Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar FXIa inhibitory activity with > 1000-fold FXa selectivity and > 100-fold thrombin selectivity. The X-ray structure of one of these inhibitors, 36, demonstrates its unique binding interactions with FXIa. Compound 32 caused a doubling of the activated partial thromboplastin time in human plasma at 2.4 mu M and was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significant role in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.