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

革兰氏阴性败血症休克的发病机制是危重病人死亡的主要原因。 是对内毒素或内毒素(脂多糖)的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类选择剂)。我们有 表明相对简单且易于合成的脂多胺类分子 与脂多糖的有毒“脂类A”部分特异结合，并中和其毒性。广泛的结构-活动 结合经典药物化学方法研究脂多胺的相互关系， 组合铅产生、分子模拟、高通量筛选和发展 新的二级和三级检测方法验证通过这些方法真正隔离内毒素的前提 体外和动物模型中的化合物已经导致了DS-96的鉴定，一种N- 烷基高香草胺衍生物。DS-的体内外内毒素隔离和中和性能研究 96与多粘菌素B不相上下，多粘菌素B是目前为止在各个方面都是金标准的脂多糖隔离剂。重要的是，在所有 我们的体内研究到目前为止，我们还无法检测到DS-96的任何明显毒性。我们建议 进一步研究DS-96的临床前开发，建立内毒素替代动物模型的疗效 电击，表征其安全性，并获得详细的药代动力学和ADME数据。

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.