Development of biomimetic oligomers as anticoagulant antagonists

描述（由申请人提供）：低分子肝素越来越多地被用于治疗深静脉血栓形成、不稳定型心绞痛和急性肺栓塞，以及在广泛的临床情况下作为血栓预防药物，包括骨科手术、高风险妊娠和癌症治疗。低分子白细胞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%的严重（危及生命的）出血与低分子肝素治疗有关，接受抗凝治疗的急性冠状动脉综合征患者出现严重出血的总死亡率增加了5倍。虽然鱼精蛋白通常用于中和冠状动脉搭桥手术后的UFH，但它不能完全逆转低分子肝蛋白或氟达肝素的抗凝作用。因此，迫切需要开发一种安全有效的LMWHs拮抗剂。目标是开发一种解毒剂，可以迅速逆转不必要的出血，同时允许快速恢复抗凝治疗，使用新剂量的低分子肝素来恢复血栓预防。我们正在开发一系列具有明确的二级或三级结构的非肽低聚物，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。与多肽相比，这些低聚物具有许多优点：相对较小的尺寸增加了稳定性并增强了组织分布，易于合成，耐蛋白水解降解，并且适合药物化学方法来微调其物理性质并优化效力和安全性。我们利用这一策略设计了与UFH和低分子肝素强烈相互作用并拮抗其抗凝血特性的小低聚物。我们建议在临床前疗效和安全性研究中评估现有先导化合物作为低分子肝素和fondaparinux拮抗剂的适用性，以确定临床候选药物。此外，我们建议继续在水杨酰胺系列和新系列芳基酰胺的药物化学方面进行努力，以确定备用化合物，以便在当前先导化合物遇到问题时替代发现程序。公共卫生相关性：低分子量肝素（LMWHs）和五糖，fondaparinux，是广泛应用于许多临床和外科应用的抗凝血剂。出血并发症是抗凝治疗中常见的不良事件。鱼精蛋白是一种有效的UFH拮抗剂，但目前还没有对五糖或低分子量肝素有效的拮抗剂。我们正在开发安全有效的非肽低聚物来中和低分子肝素和氟达哌啶的抗凝特性。

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.