A small molecule for management of filovirus hemorrhagic fevers

用于治疗丝状病毒出血热的小分子

基本信息

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
项目类别：
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

项目摘要

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(hexyl-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”)无论是暴露前治疗还是暴露后治疗，在两种模型中都同样有效。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。然后将具有最佳临床前特征的化合物进行高级体外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。