Development of biomimetic oligomers as anti-coagulant antagonists

描述（由申请人提供）：未分级肝素（UFH）和低分子量肝素（LMWHs）是广泛应用于许多临床和外科应用的抗凝血剂。与使用肝素作为抗凝治疗相关的常见不良事件是出血和肝素诱导的血小板减少症。鱼精蛋白是一种富含精氨酸的小蛋白质，是一种有效的拮抗剂，临床上用于中和UFH的抗凝作用，但目前还没有针对低分子量whs的有效拮抗剂。鱼精蛋白逆转肝素活性可引起许多不想要的血液学和血流动力学副作用。因此，临床迫切需要开发更安全的鱼精蛋白替代品来有效中和肝素的抗凝血功能。如果鱼精蛋白替代品也能有效和安全地逆转低分子量肝细胞的抗凝作用，将获得实质性的额外临床益处。许多基于蛋白质和肽的策略来模仿鱼精蛋白和鱼精蛋白的功能已经被追求，以开发一种安全有效的鱼精蛋白替代品，但非常有限的成功。作为使用肽作为蛋白质模拟物的替代策略，我们正在开发一系列具有明确定义的二级或三级结构的非肽寡聚物，作为设计靶向特定蛋白质-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。初步的文库筛选和有限的化学优化已经在两个低聚物系列中确定了推定的抗ufh先导化合物。水杨胺系列中的一种化合物（PMX60054）也显示出对一些LMWHs的有效体外活性。初步的动物研究表明，PMX60054在体内中和肝素活性方面具有与鱼精蛋白相当的效力和功效。第一阶段研究计划有两个目标：1)合成并测试其他具有体外活性的水杨酸酰胺，作为PMX60054的备用化合物，适合进入动物疗效和安全性研究；2)在动物实验中评估PMX60054和/或备用水杨酸酰胺的有效性和安全性，以确定一种治疗指数优于鱼精蛋白的发现先导化合物，适合进一步开发。未分离肝素（UFH）和低分子量肝素（LMWHs）是广泛应用于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，但目前还没有针对低分子量whs的有效拮抗剂。鱼精蛋白对UFH活性的逆转也会引起一些意想不到的副作用，包括降低心率和血压。我们正在开发非肽低聚物作为鱼精蛋白的替代品，以安全有效地中和UFH的抗凝血特性，并有可能中和LMWHs。

DESCRIPTION (provided by applicant): Unfractionated heparin (UFH) and the low molecular weight heparins (LMWHs) are widely used anti-coagulants employed in a number of clinical and surgical applications. Common adverse events associated with the use of heparin as anti-coagulant therapy are bleeding and heparin-induced thrombocytopenia. Protamine, a small arginine-rich protein, is an effective antagonist that is used clinically to neutralize the anti-coagulant effects of UFH, but presently there are no effective antagonists for the LMWHs. Protamine reversal of heparin activity can cause a number of unwanted hematological and hemodynamic side effects. Therefore, there is significant clinical need for the development of safer protamine alternatives for the effective neutralization of the anti-coagulant function of heparin. Substantial additional clinical benefit would be achieved if the protamine substitute could also effectively and safely reverse the anti-coagulant effects of the LMWHs. A number of protein and peptide-based strategies to mimic protamine and protamine function have been pursued to develop a safe and efficacious protamine substitute but with very limited success. As an alternate strategy to the use of peptides as protein mimics, 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. A preliminary library screen and limited chemical optimizations have identified presumptive anti-UFH lead compounds in two oligomer series. One of the compounds in the salicylamide series (PMX60054) also displays potent in vitro activity against some of the LMWHs. Initial animal studies have shown that PMX60054 has comparable potency and efficacy to protamine in neutralizing heparin activity in vivo. The Phase 1 research program hast two goals: 1) Synthesize and test additional salicylamides having in vitro activities suitable for moving forward into animal efficacy and safety studies as back-up compounds to PMX60054 and, 2) Evaluate the efficacy and safety of PMX60054 and/or back-up salicylamides in pilot animal studies to identify a discovery lead compound with a superior therapeutic index versus protamine suitable for further development Unfractionated heparin (UFH) and the low molecular weight heparins (LMWHs) 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 LMWHs. Protamine reversal of UFH activity can also cause a number of unwanted side effects including reductions in heart rate and blood pressure. We are developing non-peptidic oligomers as substitutes for protamine to safely and effectively neutralize the anti-coagulation properties of UFH and potentially the LMWHs.