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：
8725756
负责人：
HEIDI E HAMM
金额：
$ 34万
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/8725756
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）：此项资助是为了响应 PAR-12-060，“体内化学探针发现的验证命中征集”。血小板在血栓形成中发挥着关键作用，血栓形成是死亡和发病的主要原因。急性冠脉综合征和脑血管损伤的医疗治疗以抗血小板治疗为中心。凝血酶受体拮抗剂 (TRA) 在临床医学中备受期待，但 Vorapaxar（一种针对 PAR1 的 TRA）最近在 III 期临床试验中显示，可增加临床上显着的出血，包括颅内出血。 PAR4 是血栓形成和脑血管损伤抗血小板治疗的一个有吸引力的靶点。由于 PAR4 对凝血酶的亲和力较低，因此随着更多凝血酶的积聚，它会在 3D 凝块部位局部激活。由于 PAR4 激活的延迟，我们假设 PAR4 拮抗作用可能不会有效地影响止血，因此可能是比 PAR1 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点。然而，尚无有效的体内PAR4拮抗剂来研究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了解有限。抑制 PAR4 不会干扰通过 PAR1 受体的信号传导，而 PAR1 受体对于损伤期间的基本止血至关重要。 PAR4拮抗剂YD-3的理化性质较差，在可接受的载体中几乎没有溶解度；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、效力和选择性，以便更好地了解 PAR4 在血栓形成和止血中的作用。我们建议 1) 使用文库方法优化 PAR4 的小分子拮抗剂，2) 确定优化化合物对 PAR4 的选择性，3) 使用体外和体内 DMPK 技术确定新型 PAR4 拮抗剂的代谢和处置，以及 4)在血栓形成模型中测试优化的化合物。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制，以及对体内血栓形成模型的影响，这些数据目前无法收集。这些研究应该提供一种有价值的工具化合物，使研究能够揭示 PAR4 作为预防和治疗性抑制病理性血栓形成的替代靶点。