Development of biomimetic oligomers as anti-coagulant antagonists

作为抗凝血拮抗剂的仿生寡聚物的开发

• 批准号: 7327298
• 负责人: RICHARD W SCOTT
• 金额: $ 10万
• 依托单位: POLYMEDIX, INC,
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2008-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7327298
• 关键词: Acute; Adverse effects; Adverse event; Affect; Animals; Back; Binding; Biomimetics; Blood Pressure; Chemicals; Clinical; Clinical Research; Coagulants; Coagulation Process; Complement Activation; Development; Dose; Drug or chemical Tissue Distribution; Ensure; Goals; Heart Rate; Hemorrhage; Heparin; Heparin Antagonists; Heparin Binding; In Vitro; Inorganic Sulfates; Lead; Libraries; Low-Molecular-Weight Heparin; Membrane Proteins; Modeling; Numbers; Operative Surgical Procedures; Peptides; Pharmaceutical Chemistry; Phase; Polysaccharides; Process; Property; Protamines; Proteins; Rattus; Research; Resistance; Safety; Series; Structure; Testing; Therapeutic Index; Thrombocytopenia; Toxic effect; Unspecified or Sulfate Ion Sulfates; base; clinically relevant; cytotoxicity; design; hemodynamics; human ARMET protein; in vivo; novel; numb protein; physical property; pre-clinical; programs; response; salicylamide; size; success

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.

描述(申请人提供)：普通肝素(UFH)和低分子肝素(LMWHs)是广泛使用的抗凝血剂，在许多临床和外科应用中使用。与使用肝素作为抗凝治疗相关的常见不良事件有出血和肝素引起的血小板减少。鱼精蛋白是一种富含精氨酸的小蛋白，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肝素的有效拮抗剂。鱼精蛋白逆转肝素活性可能会引起一些不必要的血液和血流动力学副作用。因此，临床上有必要开发更安全的鱼精蛋白替代品，以有效中和肝素的抗凝功能。如果鱼精蛋白替代品也能有效和安全地逆转低分子肝素的抗凝作用，将获得实质性的额外临床益处。为了开发一种安全有效的鱼精蛋白替代品，人们寻求了许多基于蛋白质和多肽的策略来模拟鱼精蛋白和鱼精蛋白的功能，但成功非常有限。作为多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。初步的文库筛选和有限的化学优化已经在两个齐聚物系列中鉴定了假定的反UFH先导化合物。水杨酰胺系列中的一种化合物(PMX60054)在体外也显示出对一些低分子肝素的有效活性。初步的动物研究表明，PMX60054在体内具有与鱼精蛋白类似的中和肝素活性的效力和效果。第一阶段研究计划有两个目标：1)合成和测试更多具有体外活性的水杨酰胺，作为PMX60054的备用化合物进入动物疗效和安全性研究；2)在试验性动物试验中评估PMX60054和/或备用水杨酰胺的有效性和安全性，以确定发现的治疗指数高于鱼精蛋白的先导化合物，适合进一步开发普通肝素(UFH)和低分子肝素(LMWHs)是在许多临床和外科应用中广泛使用的抗凝剂。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，但目前尚无有效的低分子肝素拮抗剂。鱼精蛋白逆转UFH活性也会导致一些不良的副作用，包括心率和血压的降低。我们正在开发非肽低聚物作为鱼精蛋白的替代品，以安全和有效地中和UFH和潜在的低分子肝素的抗凝性能。