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。但是，所有当前的抗凝剂与内部出血的重大风险有关，随后限制了它们在各种中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，不要引起出血并发症，以便安全地用于更广泛的血栓形成患者。因此，该项目旨在通过靶向proc凝蛋白酶来开发有效和安全的抗凝剂凝血的固有途径，特别是因子XIA（FXIA）和/或XIIA（FXIIA）。临床使用抗凝剂直接或间接地抑制凝血途径的凝血酶和/或因子Xa。这就是它们在临床上有效的原因，但这也是它们引起出血的原因。这中心假设是抑制内在途径的人类FXIA或FXIIA将导致有效防止动脉和静脉血栓形成，而不会引起出血。 FXIA或FXIIA的抑制剂将主要防止血栓形成，并将止血过程基本完整。在初步研究，我确定了一种磺化的肽瘤，该肽构菌以适度的效力抑制FXIA，并对凝血酶和Xa因子的选择性显着。我还确定了一个苯甲酰胺，该苯甲酰胺是正向抑制的 FXIIA具有高效力和对一组相关蛋白酶的明显选择性。不仅如此，而且每个这两种抑制剂还依赖于剂量延长人血浆的凝结时间时通过内在途径启动，该途径进一步支持其功能的特异性。因此，两个 FXIA和FXIIA的抑制剂表现出非常有前途的概况，作为有效且可能安全的抗凝剂，但他们的药物和药理特性需要进一步改进。因此，我专门针对； 1）化学合成磺化的磺化变构抑制剂的高级文库并评估其生化和生物学潜力作为抗凝剂，2）化学合成一个高级文库基于苯甲酰胺的正构抑制剂FXIIA，并评估其生化和生物学潜力抗凝剂。该提议具有创新性，因为i）提出了一种新颖的方法来克服当前血栓形成治疗的局限性； ii）它利用了一种高度集成的多学科方法，涉及合成药物化学，酶动力学，分子建模和人血浆中的测试调查具体目标； iii）它引入了具有专有结构和机械性的新技术方面。该项目也很重要，因为它将识别2-4个有效和选择性抑制剂在血栓形成和出血的动物模型中，固有的凝血途径可用于将来评估。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Factor XIIIa inhibitors as potential novel drugs for venous thromboembolism.

DOI：
10.1016/j.ejmech.2020.112442
发表时间：
2020-08-15
期刊：
European journal of medicinal chemistry
影响因子：
6.7
作者：
Al-Horani RA;Kar S
通讯作者：
Kar S

Factor XI(a) inhibitors for thrombosis: an updated patent review (2016-present).

DOI：
10.1080/13543776.2020.1705783
发表时间：
2020-01
期刊：
Expert opinion on therapeutic patents
影响因子：
6.6
作者：
Al-Horani RA
通讯作者：
Al-Horani RA

Potential Therapeutic Benefits of Dipyridamole in COVID-19 Patients.

DOI：
10.2174/1381612826666201001125604
发表时间：
2021
期刊：
Current pharmaceutical design
影响因子：
3.1
作者：
Aliter KF;Al-Horani RA
通讯作者：
Al-Horani RA

4-(Imidazo[1,2-a]pyridin-3-yl): pyrimidine derivatives as anticancer agents.

4-(咪唑并[1,2-a]吡啶-3-基)：作为抗癌剂的嘧啶衍生物。

DOI：
10.4155/ppa-2022-0033
发表时间：
2023
期刊：
Pharmaceutical patent analyst
影响因子：
1.3
作者：
Al-Horani,RamiA
通讯作者：
Al-Horani,RamiA

Sulphated penta-galloyl glucopyranoside (SPGG) is glycosaminoglycan mimetic allosteric inhibitor of cathepsin G.

硫酸化五没食子酰吡喃葡萄糖苷 (SPGG) 是组织蛋白酶 G 的糖胺聚糖模拟变构抑制剂。

DOI：
10.1093/rpsppr/rqad001
发表时间：
2023-01
期刊：
RPS pharmacy and pharmacology reports
影响因子：
0
作者：
Al-Horani, Rami A;Afosah, Daniel K;Kar, Srabani;Aliter, Kholoud F;Mottamal, Madhusoodanan
通讯作者：
Mottamal, Madhusoodanan