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

革兰氏阴性脓毒性休克是危重患者死亡的主要原因， 是对内毒素或脂多糖（LPS）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Select Agent）。我们有 显示了脂多胺类的相对简单和合成容易获得的分子 特异性结合LPS的毒性“脂质A”部分并中和其毒性。广泛构效关系 使用经典药物化学方法的组合对脂多胺的关系研究， 组合先导物生成、分子建模、高通量筛选以及 新的二级和三级水平的测定，以验证的前提下，真正隔离的LPS，这些 化合物在体外以及在动物模型中的研究已经导致了DS-96的鉴定， 烷基高精胺衍生物。在体外和体内LPS螯合和中和性能的DS- 96与多粘菌素B（迄今为止在各方面都是金标准LPS螯合剂）的量相当。重要的是，在所有 到目前为止，我们的体内研究尚未检测到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，确定内毒素替代动物模型的疗效 休克，描述其安全性特征，并获得详细药代动力学和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.