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LFM-A13 for Prevention of Fatal Thromboembolism

LFM-A13 用于预防致命血栓栓塞

基本信息

批准号：
6549263
负责人：
SANDEEP MAHAJAN
金额：
$ 10万
依托单位：
PARADIGM PHARMACEUTICALS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-15 至 2003-02-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6549263
关键词：
biotherapeutic agent blood blood toxicology cardiovascular disorder prevention collagen dosage drug design /synthesis /production drug discovery /isolation drug screening /evaluation hematology laboratory mouse pharmacokinetics platelet aggregation inhibitors protein tyrosine kinase thromboembolism vascular endothelium

项目摘要

DESCRIPTION (provided by applicant): The development of a platelet-rich thrombus on damaged endothelium or atherosclerotic plaques can severely impair the blood flow to vital organs, including the brain, heart, lungs, and kidneys. The contribution of platelets to the pathogenesis of potentially fatal ischemic and/or thromboembolic events, including stroke, myocardial infarct, and pulmonary embolism, is well documented. Therefore, the discovery of effective modulators of platelet function that can prevent thrombus formation is the focus of intensified efforts in translational hematology and cardiovascular biology research.The rationally designed small molecule chemical compound a-cyano-Beta-hydroxy-Beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13) is a specific inhibitor of the TEC family protein tyrosine kinases, Bruton's tyrosine kinase (BTK) and TEC. Both BTK and TEC play an important role in platelet physiology by regulating the glycoprotein GPVI-FcRy-coupled collagen receptor signaling pathway. We have recently found that LFM-A13 inhibits (a) collagen-induced BTK/TEC stimulation, (b) BTK/TEC-dependent downstream signaling events, (c) biochemical and ultrastructural changes indicative of platelet activation, and (d) collagen-induced platelet aggregation. LFM-A13 was not toxic to mice when administered systemically at dose levels ranging from 1 mg/kg to 100 mg/kg. At nontoxic dose levels, LFM-A13 prolonged the tail bleeding times of mice and improved event-free survival in two mouse models of fatal pulmonary thromboembolism.An oral capsule formulation of LFM-A13 (LFM-A13-F) was developed and showed excellent bioavailability both in mice and dogs. We are now proposing to test the activity of this clinically applicable oral formulation in a mouse model of collagen-induced fatal thromboembolism. After establishing the single agent activity of LFM-A 13-F, we will also examine its antithrombotic effects in combination with the standard antiplatelet agents, dipyndamole or aspirin (alone or in combination). Also examined will be the effect of LFM-A13 alone or in combination with other drugs on the bleeding/clotting times in mice.

描述(申请人提供)：在受损的内皮细胞或动脉粥样硬化斑块上形成富含血小板的血栓会严重损害流向重要器官的血液，包括大脑、心脏、肺和肾脏。血小板在潜在的致命的缺血性和/或血栓栓塞性事件的发病机制中的作用，包括中风、心肌梗死和肺栓塞，是有很好的文献记载的。因此，寻找有效的血小板功能调节剂来预防血栓的形成是翻译血液学和心血管生物学研究的重点。设计合理的小分子化合物a-cyano-Beta-hydroxy-Beta-methyl-N-(2，5-dibromophenyl)-propenamide(LFM-A13)是一种特异性的TEC家族蛋白酪氨酸激酶、布鲁顿酪氨酸激酶和TEC的抑制剂。BTK和TEC通过调节糖蛋白GPVI-FcRy偶联的胶原受体信号通路，在血小板生理过程中发挥重要作用。我们最近发现LFM-A13抑制(A)胶原诱导的BTK/TEC刺激，(B)依赖于BTK/TEC的下游信号事件，(C)指示血小板激活的生化和超微结构变化，以及(D)胶原诱导的血小板聚集。当系统给药剂量从1毫克/公斤到100毫克/公斤时，LFM-A13对小鼠没有毒性。在无毒剂量水平下，LFM-A13延长了小鼠的尾部出血时间，并提高了两种致死性肺血栓栓塞症小鼠的无事件存活率。开发了LFM-A13口服胶囊制剂(LFM-A13-F)，并在小鼠和狗身上显示了良好的生物利用度。我们现在建议在胶原蛋白诱导的致命性血栓栓塞症的小鼠模型中测试这种临床适用的口服制剂的活性。在确定LFM-A13-F的单药活性后，我们还将检查其与标准抗血小板药物双潘达莫或阿司匹林(单独或联合使用)的抗血栓作用。还将研究LFM-A13单独或与其他药物联合使用对小鼠出血/凝血时间的影响。