Development of biomimetic oligomers as anticoagulant antagonists

描述(申请人提供)：低分子肝素正被更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，以及广泛的临床情况下的血栓预防药物，包括整形外科手术、高危妊娠和癌症治疗。低分子肝素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，与低分子肝素治疗相关的1%至4%的重大(危及生命)出血，而接受抗凝治疗并发生重大出血的急性冠脉综合征患者的总死亡率增加5倍。虽然鱼精蛋白通常用于中和冠状动脉旁路手术后的UFH，但它不能完全逆转低分子肝素或磺达肝素的抗凝作用。因此，医学上迫切需要开发一种安全有效的低分子肝素拮抗剂。目标是开发一种解毒剂，可以迅速逆转不想要的出血，同时允许使用新剂量的低分子肝素快速恢复抗凝治疗，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低聚物，作为针对特定蛋白质-蛋白质和蛋白质-膜相互作用的化合物设计的新模板。与多肽相比，这些低聚物具有许多优点：相对较小的尺寸可以增加稳定性和增强组织分布，易于合成，抗蛋白质降解，适合用于药物化学方法来微调其物理性质，优化效力和安全性。我们已经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性能的小分子低聚物。我们建议评估当前先导化合物作为LMWH和磺达肝素拮抗剂在临床前有效性和安全性研究中的适用性，旨在确定临床候选药物。此外，我们建议继续在水杨酰胺系列和较新的芳胺系列中进行药物化学努力，以确定备用化合物，以便在当前的先导化合物遇到问题时替代到发现计划中。公共卫生相关性：低分子肝素(LMWHs)和五糖磺达肝素广泛应用于临床和外科手术中。出血并发症是与抗凝治疗相关的常见不良事件。鱼精蛋白是一种有效的UFH拮抗剂，但目前还没有针对五糖或低分子肝素的有效拮抗剂。我们正在开发安全有效的非肽低聚物，以中和低分子肝素和磺达肝素的抗凝性能。

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.