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: 8850806
• 负责人: Timothy M Block
• 金额: $ 95.03万
• 依托单位: BARUCH S. BLUMBERG INSTITUTE
• 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/8850806
• 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; Health; 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; 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)：这是一项建议，旨在了解、优化和推进一种领先的候选小分子亚胺糖，用于控制埃博拉病毒和马尔堡病毒中的一种或两种感染人类。我们已经在体外确定了具有纳摩尔活性的亚氨酸铅糖，甚至在埃博拉和马尔堡病毒感染的小鼠致死模型中也是如此。简而言之，我们实现了对感染致命剂量埃博拉或马尔堡病毒的小鼠高达70%的保护，剂量为25-50毫克/公斤的相同亚胺糖。亚氨基糖N-cyclohexyl-N-(6-((2R，3R，4R，5S)-3，4，5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)pivalamide(己基-Pival-dnj，“17028”)和(2R，3R，4R，5S)-1-(6-(2，5-difluorophenoxy)hexyl)-2-(hydroxymethyl)piperidine-3，4，5-triol(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。然而，只有腹膜腔内(Ip)。进行了给药研究，口服可用化合物是首选。但是，含有亚氨基糖的DNJ，如我们的铅，在口服时与胃肠道(GI)痛苦有关，因为驻留的肠腔葡萄糖苷酶受到抑制。因此，将对亚氨基糖进行“药物前”修饰，以提高复方口服生物利用度并减少对GI赛道的影响。具有最佳临床前特征的化合物将在体外进行高级测试 以及体内吸收、分布、代谢、排泄和毒性(ADMET)，以及在多种动物模型中对抗马尔堡和埃博拉病毒感染的高级疗效研究。总而言之，尽管我们的两个先导药物可以向前发展成为一种非肠道给药，但人们更倾向于选择一种没有GI葡萄糖苷酶抑制活性的口服药物。因此，当前的先导药物或第二代前药将在该项目结束时准备好与我们的商业化合作伙伴一起进行IND支持研究。