A small molecule for management of filovirus hemorrhagic fevers

用于治疗丝状病毒出血热的小分子

• 批准号: 8474351
• 负责人: Timothy M Block
• 金额: $ 87.32万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8474351
• 关键词: Adverse effects; Animal Model; Animals; Antiviral Agents; Back; Biological Assay; Biological Availability; Blood Circulation; Cavia; Cell Culture Techniques; Cell Membrane Permeability; Cessation of life; Clinical; Cultured Cells; Data; Development; Distress; Dose; Drug Kinetics; Ebola virus; Endoplasmic Reticulum; Excretory function; Experimental Animal Model; Filovirus; Frankfurt-Marburg Syndrome Virus; Generations; Glucosidase Inhibitor; Goals; Human; In Vitro; Infection; Intestines; Intracellular Space; Investigation; Lead; Maximum Tolerated Dose; Metabolic; Metabolism; Modeling; Modification; Mus; Oral; Pharmaceutical Preparations; Phase; Procedures; Prodrugs; Property; Prophylactic treatment; Testing; Toxic effect; Toxicity Tests; Validation; Viral Hemorrhagic Fevers; Virus; Virus Diseases; absorption; base; biodefense; biothreat; clinical application; commercialization; design; drug biological activity; drug modification; gastrointestinal; glucosidase; hemorrhagic fever virus; improved; in vivo; intraperitoneal; meetings; milligram; mouse model; nonhuman primate; pill; piperidine; pre-clinical; preference; prevent; public health relevance; safety study; scale up; screening; small molecule; sugar

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.

描述（由申请人提供）：这是一项了解、优化和推进主要候选小分子亚氨基糖的提案，用于管理人类感染埃博拉病毒和马尔堡病毒之一或两者。我们已经在体外，甚至在埃博拉和马尔堡病毒感染的小鼠致死模型中，鉴定出具有纳摩尔级抗多种出血热病毒活性的铅亚氨基糖。简而言之，使用 25-50 毫克/公斤剂量的相同亚氨基糖，我们对感染致死剂量埃博拉病毒或马尔堡病毒的小鼠实现了高达 70% 的保护。亚氨基糖N-环己基-N-(6-((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)己基)新​​戊酰胺(己基-新戊-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”）在两种模型中的效果相似，无论是暴露前还是暴露后治疗。然而，仅进行了腹膜内（i.p.）给药研究，并且优选口服化合物。但是，含有亚氨基糖的 DNJ（例如我们的先导药物）在口服时会导致胃肠道 (GI) 不适，因为它会抑制肠腔内的葡萄糖苷酶。因此，将对亚氨基糖进行“前药”修饰，以提高化合物的口服生物利用度并减少对胃肠道的影响。具有最佳临床前特征的化合物将在体外进行高级测试 在多种动物模型中针对马尔堡病毒和埃博拉病毒感染进行体内吸收、分布、代谢、排泄和毒性 (ADMET) 以及高级功效研究。总而言之，尽管我们的两个先导药物可以作为肠胃外给药药物进行开发，但首选的是缺乏胃肠道葡萄糖苷酶抑制活性的口服药物。因此，到本项目结束时，当前的先导药物或第二代前药都将与我们的商业化合作伙伴一起准备好进行 IND 启用研究。