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

基本信息

批准号：
8049152
负责人：
Sunil A David
金额：
$ 35.01万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
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/8049152
关键词：
Acute Albumins Animal Model Animals Archives Binding Biological Assay Bioterrorism Brucella abortus Burkholderia mallei Burkholderia pseudomallei 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

项目摘要

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（由申请人提供）：革兰氏阴性败血性休克是危重患者死亡的主要原因，其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) 产生压倒性先天免疫反应的结果。 -阴性细菌（包括A类和B类选择菌）。我们已经证明，相对简单且易于合成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。结合经典药物化学方法、组合先导化合物生成、分子建模、高通量筛选以及新型二级和三级检测的开发，对脂多胺进行广泛的结构-活性关系研究，以验证脂多糖真正隔离的前提这些化合物在体外和动物模型中得到了 DS-96 的鉴定，DS-96 是一种 N-烷基高精胺衍生物。 DS-96 的体外和体内 LPS 螯合和中和特性可与多粘菌素 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建立疗效，表征其安全性，并获得详细的药代动力学和 ADME 数据。