Allosteric Inhibitors of Coagulation Proteases

凝固蛋白酶的变构抑制剂

基本信息

批准号：
9126593
负责人：
Umesh Ramanlal Desai
金额：
$ 50.93万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9126593
关键词：
Adult Affect Anticoagulant therapy Anticoagulants Anticoagulation Antidotes Antithrombin III Benzofurans Binding Binding Sites Bioavailable Biological Availability Bleeding time procedure Carotid Arteries Coagulation Process Disease Drug Delivery Systems Drug Design Drug Interactions Drug Kinetics Elements Equilibrium Factor XIa Fibrinolytic Agents Functional disorder Generations Glycosaminoglycans Goals Grant Health Hemorrhage Hemostatic Agents Hemostatic function Heparin Heparitin Sulfate Housing Human In Vitro Individual Inorganic Sulfates Investigational Drugs Lead Left Legal patent Libraries Modeling Morbidity - disease rate Oral Paper Pathway interactions Peptide Hydrolases Pharmaceutical Preparations Physicians Primates Process Property Regulation Research Research Personnel Risk Safety Specificity Surgeon System Tail Therapeutic Thrombin Thromboplastin Thrombosis Time Toxic effect Triad Acrylic Resin Unspecified or Sulfate Ion Sulfates Venous Warfarin Work X-Ray Crystallography analog base carboxylate clinically relevant design dimer high throughput screening in vivo inhibitor/antagonist innovation lead sulfate mimetics mortality mouse model novel pre-clinical preclinical study programs prophylactic scaffold structural biology

项目摘要

DESCRIPTION (provided by applicant): This project attempts to develop novel molecules as allosteric anticoagulants of coagulation proteases, especially thrombin and factor XIa. The hypothesis is that targeting these proteases through allosteric disruption of their catalytic triad results in controlled inhibition, which is likely to not suffer from bleeding consequences. All current anticoagulants including the heparins, warfarin, dabigatran and rivaroxaban suffer from enhanced risk of bleeding. The past grant period resulted in two groups of highly promising inhibitors of thrombin and factor XIa. The thrombin inhibitors displayed regulatory features (maximal inhibition in the region of 50 - 75%), which is likely to maintain hemostasis, especially under prophylactic application. Likewise, factor XIa inhibitors are likely to be devoid of bleeding because of the inherent mechanism of action of factor XIa, which is its action on the thrombotic process while leaving hemostatic process intact. In addition, the allosteric inhibitors are predicted to possess a higher specificity of action, which would reduce off target effects. Thus, the two groups of inhibitors are predicted to lead to a safer anticoagulant therapy. In fact, we have found that one of our designed molecules showed marked anticoagulant activities in FeCl3-induced thrombosis in the carotid artery mouse model without affecting bleeding time supporting the hypothesis. In this grant period, we intend to I) design more potent, selective regulators of human thrombin; II) develop more potent, selective inhibitors of human factor XIa and III) perform pre-clinical studies on promising advanced thrombin regulators and FXIa inhibitors.

描述（由应用提供）：该项目试图开发新的分子作为凝血蛋白酶的变构抗凝剂，尤其是凝血酶和因子Xia。假设是，通过变构中断催化三合会来靶向这些蛋白酶导致受控抑制作用，这可能不会遭受出血后果。所有当前的抗凝剂，包括肝素，华法林，达比加特兰和里瓦罗沙班的患者，都因增加出血风险而受害。过去的赠款期导致了两组高度有希望的凝血酶和因子XIA抑制剂。凝血酶抑制剂显示出调节特征（50-75％的最大抑制作用），这可能会维持止血，尤其是在预防性应用下。同样，因子XIA抑制剂可能没有出血由于因子因子的继承机制，这是其对血栓形成过程的作用，同时使止血过程完整。此外，预计变构抑制剂具有更高的作用特异性，这将减少靶向影响。这两组抑制剂预计将导致安全的抗凝治疗。实际上，我们发现我们设计的一个分子在颈动脉小鼠模型中显示出在FECL3诱导的血栓形成中显示出明显的抗凝活性，而不会影响支持该假设的出血时间。在这个赠款期间，我们打算i）设计人类凝血酶的更多潜力，选择性调节剂； ii）对人为因素XIA和III产生更多潜力，选择性抑制剂）对有希望的晚期凝血酶调节剂和FXIA抑制剂进行临床前研究。