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

• 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
• 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

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.

项目总结 尽管心脏病和中风的死亡率在过去40年里大幅下降，但这些血栓形成 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种新的抗血小板药物 用于控制血栓形成风险和治疗的化合物。血小板在血栓形成中起着关键作用， 死亡和发病的主要原因。急性冠脉综合征与脑血管疾病的内科处理 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)在血小板中用于产生止血塞。人类血小板既有PAR1，又有高亲和力 在血管壁止血的凝血酶受体和低亲和力凝血酶受体PAR4 它在凝块中被缓慢激活，因为它需要大量凝血酶的积累。我们的指导性假设 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 当更多的凝血酶积聚时，它在3D血栓处的局部激活。我们假设PAR4杆 拮抗可能会使血管中的凝块减少，但不会对止血产生很大影响，因此可能 减少出血副作用，成为更好的抗血小板治疗靶点。黑人有显著的 心脏病和中风的发病率更高，存活率更低。最近，一种过度活跃的PAR4等位基因是 发现并发现在63%的黑人中发生，但在白人中只有16%。我们已经使用了HTS和Medical 化学获得阻断两个等位基因的PAR4的Nm和Pm亲和拮抗剂。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 鸵鸟分流血栓模型的建立。我们将1)使用文库优化最佳的PAR4拮抗剂系列 方法，2)确定化合物的选择性和效力，弘扬具有多样性的化合物 最大限度地提高安全性的作用方式3)决定了这些药物的药代动力学、代谢和处置 PAR4拮抗剂在体外和人的体内以及在狒狒的体内，以及4)优化的化合物在 人的血小板处于血流和分流状态下的血栓形成模型。完成这些目标将提供 在灵长类动物血栓形成模型中有证据表明，PAR4拮抗是安全有效的。长期目标是 证明PAR4可作为预防和治疗病理抑制的替代靶点 血栓形成。对抗过度活跃的PAR4等位基因的拮抗剂可能有可能 发展成为一种理想的抗血小板药物，可以减少血栓形成结局的种族差异 事件。