Targeting PAR4 in Thrombotic Disorders:Pharmacogenomic Approach

血栓性疾病中的靶向 PAR4：药物基因组学方法

基本信息

批准号：
9900857
负责人：
HEIDI E HAMM
金额：
$ 75.49万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900857
关键词：
3-Dimensional Acute Address Affinity Alleles Antiplatelet Drugs Aspirin Bioavailable Biological Biological Availability Bleeding time procedure Blood Platelets Blood flow Cardiovascular system Cessation of life Chemicals Clinical Coagulation Process Collagen Coronary Arteriosclerosis Data Deposition Drug Kinetics Ensure Event F2R gene Fibrin Future G-Protein-Coupled Receptors Generations Goals Grant Heart Diseases Hemorrhage Hemostatic Agents Hemostatic function Hour Human Hyperactive behavior Impairment In Vitro Incidence Injury Integrins Lead Libraries Ligands Link Measures Mediating Medical Metabolism Modeling Molecular Weight Morbidity - disease rate Oral Outcome Papio Pathologic Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Pharmacology Plasma Play Population Prevention Preventive Primates Problem Solving Property Protease Inhibitor Proteinase-Activated Receptors Prothrombin time assay Race Radiolabeled Rattus Recurrence Risk Management Role Safety Series Shunt Device Signal Transduction Site Solid Staging Stroke Surface Testing Therapeutic Thrombin Thrombin Receptor Thrombosis Thrombus Time Tissues Vascular Graft Venous Work acute coronary syndrome cerebrovascular clopidogrel drug distribution drug metabolism druggable target improved in vivo inhibitor/antagonist mortality novel prevent protease-activated receptor 4 racial disparity side effect temporal measurement tool

项目摘要

PROJECT SUMMARY Though deaths from heart disease and stroke have fallen dramatically in the last 40 years, these thrombotic diseases are still our largest killer. The overall goal of this grant is to develop a new class of anti-platelet compounds for managing the risk and treatment of thrombosis. 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 is an essential activator of protease activated receptors (PAR) in platelets for generation of a hemostatic plug. Human platelets have both PAR1, the high-affinity thrombin receptor that underlies hemostasis at the vessel wall, and PAR4, the low-affinity thrombin receptor which is activated slowly in the clot because it requires substantial thrombin build up. Our guiding hypothesis is that PAR4 is an attractive target for anti-platelet therapy in thrombosis and cerebrovascular injury, because of its local activation at the site of the 3D clot as more thrombin builds up. We hypothesize that PAR4 antagonism might minimize clot build-up in the vessel, but not affect hemostasis as potently and thus may decrease bleeding side effects and be a better therapeutic anti-platelet target. Blacks have a significantly higher incidence of heart disease and stroke and worse survival. Recently, a hyperactive PAR4 allele was discovered and found to occur in 63% of blacks but only 16% of whites. We have used HTS and medicinal chemistry to obtain nM and pM affinity antagonists of PAR4 which block both alleles. We propose to optimize bioavailability, potency, and selectivity of our lead molecules for both of these PAR4 alleles and test them in a baboon shunt model of thrombosis. We will 1) optimize the best series of PAR4 antagonists using a library approach, 2) determine selectivity and potency of compounds, and carry forward compounds that have diverse modes of action to maximize safety 3) determine the pharmacokinetics, metabolism and disposition of these PAR4 antagonists in vitro in baboon and human and in vivo in baboon, and 4) test the optimized compound in human platelets under flow and in a baboon shunt model of thrombosis. Completion of these aims will provide evidence in primate models of thrombosis that PAR4 antagonism is safe and efficacious. The long-term goal is to demonstrate PAR4 as an alternative target for preventive and therapeutic suppression of pathologic thrombus formation. An antagonist that is active against the hyperactive PAR4 allele may have the potential to develop into an ideal anti-platelet agent that can decrease the racial disparity of outcomes of thrombotic events.

项目概要尽管过去 40 年来心脏病和中风导致的死亡人数急剧下降，但这些血栓疾病仍然是我们最大的杀手。这笔赠款的总体目标是开发一类新型抗血小板药物用于管理血栓形成风险和治疗血栓形成的化合物。血小板在血栓形成过程中发挥着重要作用死亡和发病的主要原因。急性冠状动脉综合征和脑血管病的医疗治疗损伤主要集中在抗血小板治疗上。凝血酶是蛋白酶激活受体的重要激活剂（PAR）在血小板中用于生成止血塞。人类血小板同时具有 PAR1（高亲和力）血管壁止血的凝血酶受体和低亲和力凝血酶受体 PAR4 它在凝块中缓慢激活，因为它需要大量凝血酶的积累。我们的指导假设 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，因为随着更多凝血酶的积聚，其在 3D 凝块部位的局部激活。我们假设 PAR4 拮抗作用可能会最大限度地减少血管中的凝块积聚，但不会强烈影响止血，因此可能减少出血副作用，成为更好的抗血小板治疗靶点。黑人有显着心脏病和中风的发病率更高，生存率更差。最近，一个过度活跃的 PAR4 等位基因被发现并发现 63% 的黑人会出现这种情况，但白人中只有 16% 会出现这种情况。我们使用了高温超导和药用化学获得 PAR4 的 nM 和 pM 亲和力拮抗剂，其阻断两个等位基因。我们建议优化我们的先导分子对这两个 PAR4 等位基因的生物利用度、效力和选择性，并在狒狒血栓分流模型。我们将 1) 使用库优化 PAR4 拮抗剂的最佳系列方法，2）确定化合物的选择性和效力，并开发具有多种特性的化合物最大限度提高安全性的作用方式 3) 确定这些药物的药代动力学、代谢和处置狒狒和人类体内的 PAR4 拮抗剂以及狒狒体内的 PAR4 拮抗剂，以及 4) 在流动中的人类血小板和狒狒分流血栓形成模型。完成这些目标将提供灵长类血栓形成模型的证据表明 PAR4 拮抗剂是安全有效的。长期目标是证明 PAR4 作为预防和治疗性抑制病理学的替代靶点血栓形成。一种对过度活跃的 PAR4 等位基因具有活性的拮抗剂可能有潜力发展成为一种理想的抗血小板药物，可以减少血栓形成结果的种族差异事件。