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：
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
项目类别：
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

项目摘要

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。