Preclinical development of DS-96, a novel alkylpolyamine endotoxin squestrant

新型烷基多胺内毒素螯合剂 DS-96 的临床前开发

• 批准号: 7878357
• 负责人: Sunil A David
• 金额: $ 3.52万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-14 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878357
• 关键词: Acute; Albumins; Animal Model; Animals; Archives; Binding; Biological Assay; Bioterrorism; Brucella abortus; Burkholderia mallei; Categories; Cause of Death; Clinical; Complex; Coxiella burnetii; Critical Illness; Data; Development; Differential Scanning Calorimetry; Dose; Drug Formulations; Drug Kinetics; Endotoxic Shock; Endotoxins; Evaluation; Francisella tularensis; Generations; Goals; Gold; Gram-Negative Bacteria; Harvest; Hepatocyte; Hour; Human; Immune response; In Vitro; Individual; Injection of therapeutic agent; Lead; Lethal Dose 50; Ligation; Lipid A; Lipopolysaccharides; Metabolic; Methods; Mission; Modeling; Molecular Models; Mus; Neutrophil Activation; Organ; Organism; Oryctolagus cuniculus; Outcome; Pathogenesis; Patients; Peritonitis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma; Polymyxin B; Preparation; Property; Puncture procedure; Rattus; Reference Standards; Research; Research Personnel; Rickettsia prowazekii; Route; Safety; Scheme; Sepsis; Septic Shock; Solutions; Sprague-Dawley Rats; Structure-Activity Relationship; Surface; Temperature; Testing; Therapeutic; Time; Toxic effect; Toxicokinetics; cohort; combinatorial; cytokine; hemodynamics; high throughput screening; in vivo; indexing; intravenous administration; liquid chromatography mass spectrometry; molecular modeling; monocyte; mortality; novel; pre-clinical; programs; protective effect; research study; response

The pathogenesis of Gram-negative septic shock, a leading cause of mortality in critically ill patients, is a consequence of the overwhelming innate immune response to endotoxins, or lipopolysaccharides (LPS), present on the surface of gram-negative bacteria (including Category A and B Select Agents). We have shown that relatively simple and synthetically easily accessible molecules of the lipopolyamine class specifically bind to the toxic "Lipid A" moiety of LPS and neutralize its toxicity. Extensive structure-activity relationship studies on lipopolyamines using a combination of classical medicinal chemistry approaches, combinatorial lead generation, molecular modeling, high-throughput screening, and the development of novel secondary and tertiary-level assays to verify the premise of true sequestration of LPS by these compounds in vitro as well as in animal models have led to the identification of DS-96, an N- alkylhomospermine derivative. The in vitro and in vivo LPS-sequestering and -neutralizing properties of DS- 96 rival that of polymyxin B, a gold standard LPS sequestrant in every respect thus far. Importantly, in all of our in vivo studies to date, we have been unable to detect any apparent toxicity for DS-96. We propose to further the preclinical development of DS-96, establish efficacy in alternate animal models of endotoxic shock, characterize its safety profile, and obtain detailed pharmacokinetic and ADME data.

革兰氏阴性败血性休克的发病机制是危重患者死亡的主要原因， 是对内毒素或脂多糖 (LPS) 产生压倒性先天免疫反应的结果， 存在于革兰氏阴性菌表面（包括 A 类和 B 类选择菌）。我们有 表明相对简单且合成容易获得的脂多胺类分子 特异性结合 LPS 的有毒“脂质 A”部分并中和其毒性。广泛的结构活性 结合经典药物化学方法对脂多胺进行关系研究， 组合先导化合物生成、分子建模、高通量筛选和开发 新颖的二级和三级测定来验证这些LPS真正隔离的前提 体外和动物模型中的化合物已导致 DS-96 的鉴定，这是一种 N- 烷基高精胺衍生物。 DS- 的体外和体内 LPS 隔离和中和特性 96 与多粘菌素 B 相媲美，多粘菌素 B 是迄今为止在各个方面的黄金标准 LPS 螯合剂。重要的是，在所有 迄今为止，我们的体内研究尚未检测到 DS-96 任何明显的毒性。我们建议 进一步推进 DS-96 的临床前开发，在内毒素替代动物模型中建立疗效 休克，表征其安全性，并获得详细的药代动力学和 ADME 数据。