Development of biomimetic oligomers as anticoagulant antagonists

作为抗凝拮抗剂的仿生寡聚物的开发

基本信息

批准号：
7867938
负责人：
RICHARD W SCOTT
金额：
$ 36.97万
依托单位：
POLYMEDIX, INC,
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-21 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7867938
关键词：
ADME Study Acute Adverse event Affect Animals Anticoagulants Anticoagulation Antidotes Back Binding Biological Assay Biomimetics Cardiac Cell Line Chemicals Chemistry Clinical Clinical Research Clinical Trials Coagulants Coagulation Process Complement Activation Complication Coronary Artery Bypass Dalteparin Death Rate Deep Vein Thrombosis Derivation procedure Development Dose Drug Kinetics Drug or chemical Tissue Distribution Electrophysiology (science)Endothelial Cells Enoxaparin Enzymes Erythrocytes Exhibits Fibrin Fibroblasts Frequencies Goals Hemorrhage Heparin Antagonists High-Risk Pregnancy Human In Vitro Investigational New Drug Application Kilogram Lead Life Light Low-Molecular-Weight Heparin Medical Membrane Proteins Methods Modeling Operative Surgical Procedures Orthopedic Surgery procedures Patients Peptides Pharmaceutical Chemistry Pharmacodynamics Pharmacology Phase Plasma Principal Investigator Process Property Protamines Protein Binding Proteins Publishing Pulmonary Embolism Rattus Regimen Reporting Research Research Design Resistance S Phase Safety Series Serum Solutions Structure Testing Therapeutic Index Toxic effect Unstable angina acute coronary syndrome animal efficacy base cancer therapy cytotoxic cytotoxicity design dosage drug development experience fondaparinux hemodynamics heparin pentasaccharide improved in vitro activity in vivo novel phase 2 study physical property preclinical efficacy preclinical evaluation programs public health relevance receptor safety study salicylamide scaffold scale up

项目摘要

DESCRIPTION (provided by applicant): LMWHs are being used with greater frequency to treat deep vein thrombosis, unstable angina, and acute pulmonary embolism, as well as thromboprophylaxis agents in a wide range of clinical situations including orthopedic surgery, high risk pregnancy, and cancer therapy. The most common complication of anticoagulation with LMWHs is hemorrhage. Many published clinical studies report 1% to 4% major (life-threatening) bleeding associated with LMWH therapy and there is a 5-fold increase in the overall death rate for acute coronary syndrome patients receiving anti- coagulant therapy that experience major bleeding. Although protamine is commonly used to neutralize UFH following coronary bypass surgery, it is unable to completely reverse the anticoagulant effects of LMWHs or fondaparinux. Therefore, there is a strong medical need for the development of a safe and effective antagonist for the LMWHs. The goal would be to develop an antidote that could rapidly reverse unwanted bleeding yet permit rapid resumption of anticoagulation therapy with a new dose of LMWH to restore thromboprophylaxis. We are developing series of non-peptidic oligomers with well-defined secondary or tertiary structures to serve as novel templates for the design of compounds targeting specific protein- protein and protein-membrane interactions. These oligomers have many advantages over peptides: relatively smaller size which increases stability and enhances tissue distribution, ease of synthesis, resistance to proteolytic degradation, and suitability for medicinal chemistry approaches to fine-tune their physical properties and optimize potency and safety. We have utilized this strategy to design small oligomers that strongly interact with UFH and LMWH and antagonize their anti-coagulation properties. We propose to evaluate the suitability of current lead compounds as antagonists to LMWH and fondaparinux in preclinical efficacy and safety studies designed to identify clinical candidates. In addition, we propose to continue medicinal chemistry efforts in the salicylamide series and a newer series of arylamides to identify back-up compounds to substitute into the discovery program if problems are encountered with the current lead compounds. PUBLIC HEALTH RELEVANCE: Low molecular weight heparins (LMWHs) and the pentasaccharide, fondaparinux, are widely used anti-coagulants employed in a number of clinical and surgical applications. Bleeding complications are common adverse events associated with anti-coagulant therapy. Protamine is an effective antagonist of UFH but presently there are no effective antagonists for the pentasaccharide or the low molecular weight heparins. We are developing safe and effective non-peptidic oligomers to neutralize the anti-coagulation properties of LMWH and fondaparinux.

描述（由申请人提供）：LMWH 越来越频繁地用于治疗深静脉血栓形成、不稳定心绞痛和急性肺栓塞，以及广泛临床情况下的血栓预防药物，包括骨科手术、高危妊娠和癌症治疗。 LMWH 抗凝最常见的并发症是出血。许多已发表的临床研究报告称，1% 至 4% 的大出血（危及生命的）与 LMWH 治疗相关，并且接受抗凝治疗的急性冠脉综合征患者发生大出血的总体死亡率增加了 5 倍。尽管鱼精蛋白通常用于中和冠状动脉搭桥手术后的 UFH，但它无法完全逆转 LMWH 或磺达肝素的抗凝作用。因此，医学界迫切需要开发安全有效的 LMWH 拮抗剂。我们的目标是开发一种解毒剂，可以快速逆转不必要的出血，同时允许使用新剂量的 LMWH 快速恢复抗凝治疗，以恢复血栓预防。我们正在开发一系列具有明确二级或三级结构的非肽寡聚物，作为设计针对特定蛋白质-蛋白质和蛋白质-膜相互作用的化合物的新模板。这些寡聚体与肽相比具有许多优点：尺寸相对较小，可提高稳定性并增强组织分布、易于合成、抗蛋白水解降解以及适合药物化学方法来微调其物理特性并优化效力和安全性。我们利用这一策略设计了与 UFH 和 LMWH 强烈相互作用并拮抗其抗凝特性的小寡聚物。我们建议在旨在确定临床候选药物的临床前疗效和安全性研究中评估当前先导化合物作为 LMWH 和磺达肝素拮抗剂的适用性。此外，我们建议继续在水杨酰胺系列和更新的芳酰胺系列方面进行药物化学工作，以确定如果当前先导化合物遇到问题，可以替代发现计划的备用化合物。公众健康相关性：低分子量肝素 (LMWH) 和五糖磺达肝素是广泛用于许多临床和外科应用的抗凝剂。出血并发症是与抗凝治疗相关的常见不良事件。鱼精蛋白是UFH的有效拮抗剂，但目前尚无五糖或低分子量肝素的有效拮抗剂。我们正在开发安全有效的非肽寡聚物来中和 LMWH 和磺达肝素的抗凝特性。