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

描述(由申请人提供)：革兰氏阴性败血症休克是危重患者死亡的主要原因，其发病机制是由于革兰氏阴性细菌(包括A类和B类选择药物)表面存在的内毒素或脂多糖(LPS)产生压倒性的天然免疫反应的结果。我们已经证明，相对简单和容易合成的脂多胺类分子能与有毒的脂多糖“脂类A”部分特异结合，并中和其毒性。使用经典药物化学方法、组合铅生成、分子建模、高通量筛选以及开发新的二级和三级分析方法来验证这些化合物在体外和动物模型中真正隔离内毒素的前提下，对脂多胺进行了广泛的构效关系研究，从而鉴定了DS-96，一种N-烷基高香草胺衍生物。DS-96在体外和体内对内毒素的隔离和中和性能与多粘菌素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内毒素隔离剂。重要的是，到目前为止，在我们所有的体内研究中，我们还无法检测到DS-96的任何明显毒性。我们建议进一步开发DS-96的临床前研究，在内毒素休克的替代动物模型上建立疗效，表征其安全性，并获得详细的药代动力学和ADME数据。

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.