Optimization of PAR4 antagonists for thrombotic disorders

治疗血栓性疾病的 PAR4 拮抗剂的优化

• 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
• 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

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）：该授权是对PAR-12-060，体内化学探针发现的验证命中请求的回应。血小板在血栓形成中起关键作用，血栓形成是死亡和发病的主要原因。急性冠状动脉综合征和脑血管损伤的药物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，但靶向PAR 1的TRA Vorapaxar最近在III期临床试验中显示可增加临床显著出血，包括颅内出血。PAR 4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PAR 4对凝血酶的亲和力低，随着更多凝血酶的积聚，它在3D凝块的部位被局部激活。由于PAR 4激活的延迟，我们假设PAR 4拮抗作用可能不会有效影响止血，因此可能是比PAR 1更好的治疗靶点。我们的主要假设是PAR 4的抑制是血栓形成和脑血管损伤中血小板抑制的潜在靶点。然而，没有PAR 4拮抗剂在体内有效地研究PAR 4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PAR 4在生理环境中的作用的理解是有限的。PAR 4的抑制不会干扰通过PAR 1受体的信号传导，这对于损伤期间的基本止血是必需的。PAR 4拮抗剂YD-3的理化性质较差，在可接受的溶媒中几乎不溶解;因此，它不适用于体内研究。我们建议优化YD- 3和相关分子的溶解度、效力和选择性，以便更好地理解PAR 4在血栓形成和止血中的作用。我们提出1）使用文库方法优化PAR 4的小分子拮抗剂，2）确定优化化合物对PAR 4的选择性，3）使用体外和体内DMPK技术确定新型PAR 4拮抗剂的代谢和处置，以及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关于PAR 4的基本药理学信息，包括受体密度、PAR 4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，这将使研究能够揭示PAR 4作为预防和治疗性抑制病理性血栓形成的替代靶点。