Optimization of PAR4 antagonists for thrombotic disorders

治疗血栓性疾病的 PAR4 拮抗剂的优化

基本信息

批准号：
8584861
负责人：
HEIDI E HAMM
金额：
$ 34.16万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584861
关键词：
3-Dimensional Affect Affinity Agonist Animal Model Aspirin Attenuated Biological Assay Bleeding time procedure Blood - brain barrier anatomy Blood Coagulation Factor Blood Platelets Blood flow Cells Cerebral Ischemia Chemicals Cleaved cell Clinical Medicine Coagulation Process Collagen Coupled Data Disease Drug Kinetics Endothelial Cells Environment Enzymes Event F2R gene Family member Fibrin Fibrinogen GTP-Binding Proteins Generations Goals Grant Hemorrhage Hemostatic function In Vitro Injury Integrins Intracranial Hemorrhages Ischemic Stroke Libraries Life Ligands Link Medical Metabolism Methods Modeling Morbidity - disease rate Mus Nerve Degeneration PAR-1 Receptor PAWR gene Pathologic Peptides Permeability Pharmaceutical Preparations Phase III Clinical Trials Physiological Platelet Activation Platelet aggregation Play Preventive Property Proteinase-Activated Receptors Recruitment Activity Reperfusion Therapy Role Signal Transduction Site Solubility Stroke Tail Techniques Testing Therapeutic Thrombin Thrombin Receptor Thrombosis Thrombus Whole Blood Work acute coronary syndrome analog base cerebrovascular clinically significant clopidogrel in vivo in vivo Model inhibitor/antagonist mortality novel pharmacodynamic model public health relevance receptor density release of sequestered calcium ion into cytoplasm response scaffold screening small molecule therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): This grant is in response to PAR-12-060, Solicitation of Validated Hits for the Discovery of in vivo Chemical Probes. Platelets play a critical role in thrombosis, the major cause of mortality and morbidity. Medical management of acute coronary syndrome and cerebrovascular injury is centered on anti-platelet therapies. Thrombin receptor antagonists (TRAs) are highly awaited in clinical medicine but Vorapaxar, a TRA that targets PAR1, was recently shown in Phase III clinical trials to increase clinically significant bleeding including intracranial hemorrhage. PAR4 is an attractive target for anti-platelet therapy in thrombosis and cerebrovascular injury. Because of PAR4's low affinity for thrombin, it is activated locally at the site of the 3D clot as more thrombin builds up. Because of this delay in activation of PAR4, we hypothesize that PAR4 antagonism might not affect hemostasis as potently and thus may be a better therapeutic target than PAR1. Our major hypothesis is that inhibition of PAR4 is a potential target for platelet inhibition in thrombosis and cerebrovascular injury. However, there are no PAR4 antagonists that are efficacious in vivo to study the role of PAR4 in thrombosis, ischemic stroke and neurodegeneration. Due to the lack of tool compounds, the field's understanding of the role of PAR4 in physiological environments is limited. Inhibition of PAR4 would not perturb signaling through the PAR1 receptor, which is essential for basic hemostasis during injury. The PAR4 antagonist YD-3 has poor physiochemical properties and virtually no solubility in acceptable vehicles; therefore, it is not suitable for in vivo studies. We propose to optimize solubility, potency, and selectivity of YD- 3 and related molecules in order to better understand the role of PAR4 in thrombosis and hemostasis. We propose to 1) optimize a small molecule antagonist of PAR4 using a library approach, 2) determine selectivity of optimized compounds for PAR4, 3) determine the metabolism and disposition of novel PAR4 antagonists using in vitro and in vivo DMPK techniques, and 4) test the optimized compound in models of thrombosis. An optimized compound will allow us to determine basic pharmacological information about PAR4 including receptor density, mechanism of action for PAR4 antagonists and agonists, and effects on in vivo models of thrombosis, data which currently cannot be collected. These studies should provide a valuable tool compound which will enable studies that may reveal PAR4 as an alternative target for preventive and therapeutic suppression of pathologic thrombus formation.

描述（由申请人提供）：该赠款是针对Par-12-060的响应，征集了经过验证的命中以发现体内化学探针。血小板在血栓形成中起着至关重要的作用，这是死亡率和发病率的主要原因。急性冠状动脉综合征和脑血管损伤的医疗管理集中在抗血小板疗法上。在临床医学中，凝血酶受体拮抗剂（TRAS）高度等待，但是靶向PAR1的VORAPAXAR最近在III期临床试验中显示，以增加临床意义的出血，包括颅内出血。 PAR4是血栓形成和脑血管损伤中抗血小板治疗的有吸引力的靶标。由于PAR4对凝血酶的低亲和力，随着更多的凝血酶的积累，它在3D凝块的位置被局部激活。由于PAR4激活的延迟，我们假设PAR4拮抗作用可能不会像PAR1那样有效地影响止血，因此可能是更好的治疗靶点。我们的主要假设是，抑制PAR4是血栓形成和脑血管损伤中血小板抑制的潜在靶标。但是，没有PAR4拮抗剂在体内有效地研究PAR4在血栓形成，缺血性中风和神经变性中的作用。由于缺乏工具化合物，该领域对PAR4在生理环境中的作用的理解是有限的。 PAR4的抑制不会通过PAR1受体扰动信号传导，这对于损伤过程中碱性止血至关重要。 PAR4拮抗剂YD-3具有较差的理化特性，并且在可接受的车辆中几乎没有溶解度。因此，它不适合体内研究。我们建议优化YD-3和相关分子的溶解度，效能和选择性，以便更好地了解PAR4在血栓形成和止血中的作用。我们建议使用库方法来优化PAR4的小分子拮抗剂，2）确定PAR的优化化合物的选择性，3）确定使用体外和体内DMPK技术的新型PAR4拮抗剂的代谢和处置，以及4）4）在血栓形成模型中测试优化化合物。优化的化合物将使我们能够确定有关PAR4的基本药理学信息，包括受体密度，PAR4拮抗剂和激动剂的作用机理以及对目前无法收集的数据的对体内血栓形成模型的影响。这些研究应提供有价值的工具化合物，该化合物将使可能揭示PAR4作为预防性和治疗性抑制病理血栓形成的替代靶标。