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: 7777823
• 负责人: Sunil A David
• 金额: $ 35.77万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777823
• 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

DESCRIPTION (provided by applicant): 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.

描述（由申请方提供）：革兰氏阴性菌感染性休克（危重患者死亡的主要原因）的发病机制是对革兰氏阴性菌表面存在的内毒素或脂多糖（LPS）（包括A类和B类选择制剂）产生压倒性先天免疫应答的结果。我们已经表明，相对简单和合成容易获得的脂多胺类分子特异性结合到LPS的毒性“脂质A”部分，并中和其毒性。使用经典药物化学方法、组合先导物生成、分子建模、高通量筛选和开发新型二级和三级水平测定的组合对脂多胺进行广泛的结构-活性关系研究，以验证这些化合物在体外以及动物模型中真正螯合LPS的前提，从而鉴定出DS-96，一种N-烷基高精胺衍生物。DS- 96的体外和体内LPS螯合和中和特性与多粘菌素B（迄今为止在各方面均为金标准LPS螯合剂）相当。重要的是，在迄今为止的所有体内研究中，我们无法检测到DS-96的任何明显毒性。我们建议进一步开展DS-96的临床前开发，在内毒素休克的替代动物模型中确定疗效，表征其安全性特征，并获得详细的药代动力学和ADME数据。