Factor XIa inhibitors: A review of the patent literature.
Factor XIa inhibitors: A review of the patent literature.
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DOI：
10.1517/13543776.2016.1154045
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发表时间：
2016
影响因子：
6.6
通讯作者：
Desai UR
中科院分区：
文献类型：
--
作者：
Al-Horani RA;Desai UR
抗凝剂是预防和/或治疗血栓性疾病的主要药物。每一种临床使用的抗凝剂都与严重的不良后果有关，尤其是出血。凝血因子Xia(FXIa)是凝血信号放大的关键因子，因其可降低出血风险，已被认为是抗凝血药物开发的主要靶点。我们的文献检索发现了数十项发现新型FXIa/FXI抑制剂的工业和学术专利。作为FXIa的抑制剂，已开发出小肽模拟物、硫酸化糖胺多糖模拟物、多肽、反义寡核苷酸和单抗。虽然许多药物处于早期发现/开发阶段，但少数药物的活性和安全性已在各种动物模型和人类身上进行了评估。FXIa是一种很有前景的药物靶点，可用于开发有效的、出血并发症少的抗凝剂。文献显示，在过去的三年中，专利申请的数量有一个主要趋势。这些抑制剂利用不同的方法进行靶向抑制。FXIa的变构调节和FXI的生物合成抑制在机制上是独特的。尽管与反义寡核苷酸一样，在膝关节成形术患者中取得了初步结果，但FXI/FXIa抑制剂进入临床仍需取得重大进展，特别是在药代动力学方面。
Anticoagulants are the mainstay for prevention and/or treatment of thrombotic disorders. Each clinically used anticoagulant is associated with significant adverse consequences, especially bleeding. Factor XIa (FXIa), a key factor involved in the amplification of procoagulation signal, has been suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. Our literature search uncovered dozens of industrial and academic patents on the discovery of novel FXIa/FXI inhibitors. Small peptidomimetics, sulfated glycosaminoglycan mimetics, polypeptides, antisense oligonucleotides, and monoclonal antibodies have been developed as inhibitors of FXIa. Although many agents are in early discovery/development phases, the activity and safety of a few have been evaluated in various animal models and in humans. FXIa is a promising drug target for development of effective anticoagulants with limited bleeding complications. Literature reveals a major trend in the number of patent applications over the last three years. These inhibitors exploit different approaches for target inhibition. Allosteric modulation of FXIa and biosynthetic inhibition of FXI are mechanistically unique. Despite initial results in patients undergoing knee anthroplasty as with antisense oligonucleotides, major advances should be realized, particularly with respect to pharmacokinetics, for FXI/FXIa inhibitors to enter the clinic.