Virginia Commonwealth University, Institute for Structural Biology and Drug Discovery, Department of Medicinal Chemistry , 800 East Leigh Street, Suite 212, PO Box 980133, Richmond, VA 23219 , USA +1 804 828 7328 ; +1 804 827 3664 ;
Expert Opin Ther Pat. 2014 Jan;24(1):47-67. doi: 10.1517/13543776.2014.845169. Epub 2013 Oct 8.
Thromboembolic incidences have increased nearly 33% in the past decade and directly affect nearly 0.5% of the population. Heparin, warfarin and current direct thrombin inhibitors (DTIs), the primary anticoagulants of choice, suffer from several drawbacks. Thus, the search for an antithrombotic devoid of adverse effect continues in earnest.
Literature search covering PubMed, SciFinder(™) Scholar, Web of Knowledge, Espacenet, PatentScope and Google Patent Search was used to uncover > 35 patents describing new chemical entities and advances in DTI technologies. Our search uncovered considerable emphasis on the development of larger more complex molecules such as peptide-based inhibitors, prodrug derivatives, bivalent tryptophan zippers, triple action inhibitors and allosteric inhibitors. Advances in formulation technologies for clinically relevant DTIs have also been made.
Thrombin is a multifaceted, dynamic enzyme with both coagulant and anticoagulant functions. Newer DTIs are attempting to fine tune thrombin's activity by targeting allosteric sites or by site-specific targeting of clotting. The complexity of thrombin's functions is driving the design of complex anticoagulants. Advancements in formulations and production processes have attempted to make traditional DTIs more cost effective to produce. The literature reveals a trend to develop a thrombin 'modulator' rather than an 'inhibitor.'
在过去的十年中，血栓栓塞事件的发生率增加了近 33%，直接影响了近 0.5%的人口。肝素、华法林和目前的直接凝血酶抑制剂（DTIs）是主要的抗凝选择，它们都存在一些缺点。因此，人们仍在不懈地寻找一种没有不良反应的抗血栓药物。
通过对 PubMed、SciFinder(™) Scholar、Web of Knowledge、Espacenet、PatentScope 和 Google Patent Search 进行文献检索，发现了>35 项描述新型化学实体和 DTI 技术进展的专利。我们的搜索发现，人们非常重视开发更大、更复杂的分子，如基于肽的抑制剂、前药衍生物、二价色氨酸拉链、三作用抑制剂和变构抑制剂。在具有临床相关性的 DTIs 的制剂技术方面也取得了进展。
凝血酶是一种多方面的、动态的酶，具有凝血和抗凝双重功能。新型 DTI 正试图通过靶向变构部位或通过特定部位靶向凝血来微调凝血酶的活性。凝血酶功能的复杂性正在推动复杂抗凝剂的设计。制剂和生产工艺的进步试图使传统的 DTIs 更具成本效益。文献表明，开发一种凝血酶“调节剂”而不是“抑制剂”的趋势。
