Inhibitors of the Intrinsic Pathway of Coagulation as New Anticoagulants

作为新型抗凝剂的内在凝血途径抑制剂

基本信息

批准号：
10377566
负责人：
Rami A Al-Horani
金额：
$ 10.65万
依托单位：
XAVIER UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-04-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377566
关键词：
Affect African American population Alkanesulfonates Animal Model Anticoagulant therapy Anticoagulants Anticoagulation Area Atrial Fibrillation Attenuated Benzamides Biochemical Biological Blood Vessels Cessation of life Chemicals Chronic Kidney Failure Clinical Clinical Research Coagulation Process Complication Deep Vein Thrombosis Development Diagnosis Dose Drug Targeting Enzyme Kinetics Ethnic group Evaluation Exhibits Factor XIIa Factor XIa Factor Xa Fright Future Goals Hand Hemodialysis Hemorrhage Hemostatic Agents Hemostatic function Human Individual Ischemic Stroke Lead Libraries Link Malignant Neoplasms Morbidity - disease rate Myocardial Ischemia Pathway interactions Patients Peptide Hydrolases Persons Pharmaceutical Chemistry Pharmacologic Substance Pharmacology Plasma Play Prevalence Process Property Prophylactic treatment Proteins Pulmonary Embolism Race Recurrence Research Risk Role Serine Protease Specificity Testing Therapeutic Thrombin Thrombosis Time Venous Thrombosis Work base burden of illness clinically relevant design epidemiology study experimental study fundamental research improved inhibitor innovation interdisciplinary approach molecular modeling mortality nanomolar new technology novel novel strategies novel therapeutics patient population peptidomimetics prevent screening small molecule thrombotic virtual screening

项目摘要

SUMMARY Anticoagulants are clinically used to prevent and/or treat thrombotic diseases. Yet, all current anticoagulants are associated with a significant risk of internal bleeding which subsequently limits their effective use in various patient populations. The long-term goal of research in this area is to introduce effective anticoagulants that do not cause bleeding complications so as to be safely used for a wider range of thrombotic patients. Thus, this project aims at developing effective and safe anticoagulants by targeting procoagulant proteases in the intrinsic pathway of coagulation, particularly factor XIa (FXIa) and/or factor XIIa (FXIIa). Clinically used anticoagulants inhibit directly or indirectly thrombin and/or factor Xa of the common pathway of coagulation. This is the reason why they are clinically effective, but it is also the reason why they cause bleeding. The central hypothesis is that inhibiting human FXIa or FXIIa of the intrinsic pathway will result in effective protection against both arterial and venous thromboses without causing bleeding. Inhibitors of FXIa or FXIIa will primarily prevent thrombosis and will leave the hemostatic process essentially intact. In preliminary studies, I identified a sulfonated peptidomimetic that allosterically inhibits FXIa with moderate potency and significant selectivity over thrombin and factor Xa. I also identified a benzamide that orthosterically inhibits FXIIa with high potency and significant selectivity over a panel of related proteases. Not only that but each of these two inhibitors also dose-dependently prolongs the clotting time of human plasma when coagulation is initiated through the intrinsic pathway which further supports their specificity of function. Therefore, the two inhibitors of FXIa and FXIIa exhibit very promising profiles as effective and potentially safe anticoagulants, yet their pharmaceutical and pharmacological properties require further improvement. Thus, I specifically aim to; 1) chemically synthesize an advanced library of sulfonated allosteric inhibitors of FXIa and evaluate their biochemical and biological potential as anticoagulants and 2) chemically synthesize an advanced library of benzamide-based orthosteric inhibitors of FXIIa and evaluate their biochemical and biological potential as anticoagulants. The proposal is innovative because i) it puts forward a novel approach to overcome the limitations of current thrombosis treatment; ii) it exploits a highly integrated, multidisciplinary approach involving synthetic medicinal chemistry, enzyme kinetics, molecular modeling, and testing in human plasmas to investigate the specific aims; and iii) it introduces new technologies with proprietary structural and mechanistic aspects. The project is also significant because it will identify 2-4 potent and selective inhibitors of the intrinsic coagulation pathway for future evaluation in animal models of thrombosis and bleeding.

概括抗凝剂在临床上用于预防和/或治疗血栓性疾病。然而，目前所有的抗凝剂与内出血的显着风险相关，这随后限制了它们在各种领域的有效使用患者人群。该领域研究的长期目标是引入有效的抗凝剂不会引起出血并发症，可安全用于更广泛的血栓患者。因此，该项目旨在通过针对促凝血蛋白酶来开发有效且安全的抗凝血剂凝血的内在途径，特别是因子 XIa (FXIa) 和/或因子 XIIa (FXIIa)。临床使用抗凝剂直接或间接抑制凝血共同途径的凝血酶和/或因子Xa。这就是它们在临床上有效的原因，但也是它们引起出血的原因。这中心假设是抑制人类 FXIa 或 FXIIa 的内在途径将导致有效的防止动脉和静脉血栓形成而不引起出血。 FXIa 或 FXIIa 抑制剂将主要防止血栓形成，并使止血过程基本完整。在初步通过研究，我发现了一种磺化肽模拟物，它可以以中等效力变构抑制 FXIa，并且对凝血酶和 Xa 因子具有显着的选择性。我还发现了一种苯甲酰胺，它可以正位抑制 FXIIa 比一组相关蛋白酶具有高效力和显着选择性。不仅如此，每一个当凝血发生时，这两种抑制剂还可以剂量依赖性地延长人血浆的凝血时间。通过内在途径启动，进一步支持其功能特异性。因此，两人 FXIa 和 FXIIa 抑制剂作为有效且潜在安全的抗凝剂表现出非常有前景的特性，但它们的药学和药理特性需要进一步改进。因此，我的具体目标是： 1) 化学合成先进的 FXIa 磺化变构抑制剂库并评估其效果作为抗凝剂的生化和生物潜力，2) 化学合成先进的库基于苯甲酰胺的 FXIIa 正位抑制剂，并评估其生化和生物学潜力抗凝剂。该提案具有创新性，因为 i) 它提出了一种新颖的方法来克服目前血栓治疗的局限性； ii) 它采用高度综合的、多学科的方法，涉及合成药物化学、酶动力学、分子建模和人体血浆测试调查具体目标； iii) 引入了具有专有结构和机械的新技术方面。该项目也很重要，因为它将鉴定 2-4 种有效的选择性抑制剂用于未来评估血栓形成和出血动物模型的内在凝血途径。