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ANALOGS OF HPMPA FOR TREATMENT OF SMALLPOX

用于治疗天花的 HPMPA 类似物

基本信息

批准号：
6998638
负责人：
Karl Y Hostetler
金额：
$ 139.17万
依托单位：
VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2007-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6998638
关键词：
DNA directed DNA polymerase Macaca fascicularis Poxviridae Poxviridae disease adenine analog antiviral agents autoradiography drug design /synthesis /production drug metabolism drug resistance drug screening /evaluation esters gene mutation laboratory mouse pharmacokinetics radiotracer toxicology vaccinia virus

项目摘要

Antiviral drugs for smallpox are urgently needed because vaccination with "Dryvax" is unsafe for many people and because IL-4-containing poxviruses can subvert vaccine-induced protection. Cidofovir (CDV), an effective anti-poxvirus drug that must be given intravenously, has been improved by conjugating it with a hexadecyloxypropyl- (HDP) moiety. The resulting HDP-CDV is orally bioavailable and is now in final testing as an anti-smallpox drug. However, a second generation drug is needed because resistance to CDV can occur, and drugs frequently fail during the final stages of testing. Consequently, lipid esters of an adenine analog, (S)-9-[3-hydroxy-(2-phosphonomethoxy)propyl]-adenine ((S)-HPMPA), were produced. The advantages of HDP-(S)-HPMPA include: in vitro antiviral potency against poxviruses >60 times that of the current lead compound but with lower toxicity; oral activity in lethal models of cowpox and vaccinia in mice; protection from death even when given to mice 3 days after vaccinia infection; and a broad spectrum of antiviral activity against all dsDNA viruses and some retroviruses, including HIV-1. The alkoxyalkyl esters of (S)-HPMPA will be assessed and developed to attain four Milestones: (1) Lead optimization of the four most promising alkoxyalkyl esters of (S)-HPMPA by testing against poxviruses (including variola) in vitro, and by assessing oral activity in lethal challenge models with vaccinia, cowpox and ectromelia in mice, in vivo. (2) Evaluation of the best drug candidate by studies on oral pharmacokinetics, tissue distribution, metabolism, development of analytical methods for drug substance, stability testing, bioanalytical methods development, and 14 day GLP toxicology and histopathology in mice. (3) Preparation for IND submission, will focus on optimization of the chemical process for manufacturing, safety toxicology and genetic toxicology studies, and oral pharmacokinetics and a 14 day GLP toxicology and histopathology analysis in cynomolgus monkeys. (4) Evaluation of resistance to HDP-(S)-HPMPA using serially passaged vaccinia-WR and development of rapid nucleic acid testing for resistance mutations in the viral DNA polymerase. In conclusion, these studies are expected to yield an excellent drug candidate for the prevention and treatment of smallpox that is expected to be very close to Phase I clinical trials. HPMPA analogs are broad spectrum antivirals and other uses are anticipated which could make commercial development more likely.

目前迫切需要针对天花的抗病毒药物，因为接种“Dryvax”疫苗对许多人来说是不安全的，而且含有IL-4的痘病毒会破坏疫苗诱导的保护作用。西多福韦（CDV），一种有效的抗痘病毒药物，必须给予静脉注射，已被改进，通过共轭它与十六烷氧基丙基-（HDP）部分。由此产生的HDP-CDV可口服生物利用，目前正在作为抗天花药物进行最终测试。然而，需要第二代药物，因为对CDV的耐药性可能发生，并且药物在测试的最后阶段经常失败。因此，产生腺嘌呤类似物的脂质酯，（S）-9-[3-羟基-（2-膦酰甲氧基）丙基]-腺嘌呤（（S）-HPMPA）。的 HDP-（S）-HPMPA的优点包括：抗痘病毒的体外抗病毒效力是目前的先导化合物的60倍以上，但毒性较低;在小鼠牛痘和牛痘的致死模型中的口服活性;即使在牛痘感染后3天给予小鼠时也能保护免于死亡;以及对所有dsDNA病毒和一些逆转录病毒（包括HIV-1）的广谱抗病毒活性。将评估和开发（S）-HPMPA的烷氧基烷基酯，以实现四个目标：（1）通过体外抗痘病毒（包括天花）测试，以及通过在小鼠体内用牛痘、牛痘和肢脱病的致死性攻击模型中评估口服活性，对（S）-HPMPA的四种最有前景的烷氧基烷基酯进行先导优化。（二）通过小鼠经口药代动力学、组织分布、代谢、原料药分析方法开发、稳定性试验、生物分析方法开发和14天GLP毒理学和组织病理学研究评价最佳候选药物。(3)IND提交的准备工作将侧重于优化用于生产的化学工艺、安全性毒理学和遗传毒理学研究、食蟹猴经口给药药代动力学和14天GLP毒理学和组织病理学分析。(4)使用连续传代的疫苗WR评价HDP-（S）-HPMPA耐药性，并开发病毒DNA聚合酶耐药性突变的快速核酸检测。总之，这些研究有望产生一种非常接近I期临床试验的用于预防和治疗天花的优秀候选药物。HPMPA类似物是广谱抗病毒药物，预期其他用途可能使商业开发更有可能。