A small molecule for management of filovirus hemorrhagic fevers

描述（由申请方提供）：这是一项旨在了解、优化和推进用于管理埃博拉病毒和马尔堡病毒中任一种或两种的人类感染的领先候选小分子亚氨基糖的提案。我们已经鉴定出具有纳摩尔活性的铅亚氨基糖在体外对抗多种出血热病毒，甚至在埃博拉和马尔堡的小鼠感染的致死模型中。简单地说，我们用25-50毫克/千克剂量的相同亚氨基糖实现了高达70%的感染致死剂量的埃博拉病毒或马尔堡病毒的小鼠的保护。亚氨基糖N-环己基-N-（6-（（2 R，3R，4 R，5S）-3，4，5-三羟基-2-（羟甲基）哌啶-1-基）己基）新戊酰胺（己基-pival-DNJ，“17028”）和（2R，3R，4R，5S）-1-（6-（2，5-二氟苯氧基）己基）-2-（羟甲基）哌啶-3，4，5-三醇（氟-己基-DNJ，“11029”）在两种模型中作为暴露前或暴露后治疗是类似有效的。然而，仅腹膜内（i. p.）进行了给药研究，优选口服化合物。但是，含有亚氨基糖的DNJ，例如我们的先导化合物，在口服时与胃肠道（GI）不适有关，因为抑制了肠道内的葡萄糖醛酸酶。因此，将对亚氨基糖进行“前药”修饰，以改善化合物口服生物利用度并减少对GI轨迹的影响。具有最佳临床前特征的化合物随后将进行高级体外试验， 和体内吸收、分布、代谢、排泄和毒性（ADMET），以及在多种动物模型中针对马尔堡和埃博拉病毒感染的高级疗效研究。综上所述，尽管我们的两种先导药物可以作为胃肠外给药药物向前发展，但首选的是缺乏GI葡萄糖苷酶抑制活性的口服药物。因此，在本项目结束时，无论是当前的先导药物还是第二代前药，都将与我们的商业化合作伙伴一起准备进行IND使能研究。

DESCRIPTION (provided by applicant): This is a proposal to understand, optimize and advance a lead candidate small molecule imino sugar forward for the management of human infection by either or both Ebola and Marburg viruses. We have identified lead imino sugars with nanomolar activity against multiple hemorrhagic fever viruses in vitro, and even in lethal models of mouse infection of Ebola and Marburg. Briefly, we achieved protection of up to 70% of the mice infected with lethal doses of either Ebola or Marburg viruses, with 25-50 milligram/kg dosing of the same imino sugar. Imino sugar N-cyclohexyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)pivalamide (hexyl-pival-DNJ, "17028") and (2R,3R,4R,5S)-1-(6-(2,5-difluorophenoxy)hexyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (fluoro-hexyl-DNJ, "11029") were similarly effective in both models, either as pre- or post-exposure treatment. However, only intraperitoneal (i.p.) administration studies were performed, and orally available compounds are preferred. But, DNJ containing imino sugars, such as our leads, have been associated with gastrointestinal (GI) distress, when taken orally, because of the inhibition of resident intestinal lumenal glucosidases. Therefore, "pro-drug" modifications to the imino sugars, to improve compound oral bioavailability and reduce effects upon the GI track, will be carried out. Compounds with the best pre-clinical profile will then be tested for advanced in vitro and in vivo Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET), and advanced efficacy studies, against both Marburg and Ebola virus infections in multiple animal models. Taken together, although our two leads could be moved forward toward development as a parenterally administered drug, the preference is for an orally available medication devoid of GI glucosidase inhibitory activity. Thus, either the current lead or a second generation prodrug will be ready for IND enabling studies, with our commercialization partner, by the end of this project.