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Optimization of HPMPA and CDV Analogs for Treatment of Smallpox

HPMPA 和 CDV 类似物治疗天花的优化

基本信息

批准号：
7787503
负责人：
Karl Y Hostetler
金额：
$ 53.61万
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：
2008
资助国家：
美国
起止时间：
2008-04-15 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7787503
关键词：
9-(3-hydroxy-2-phosphonomethoxypropyl)guanine 9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine Acquired Immunodeficiency Syndrome Animal Model Animals Antiviral Agents Area Under Curve Bioterrorism Bypass Carbon Cells Cessation of life Chemical Structure Chemotherapy-Oncologic Procedure Cidofovir Clinical Cowpox Cytochrome P450 DNA-Directed DNA Polymerase Development Disease Dose Dose-Limiting Drug Kinetics Ectromelia Enzymes Esters Evaluation FDA approved Family Gastrointestinal Transit Gastrointestinal tract structure Government Guanine HIV Hepatic Immune Immunosuppression In Vitro Infection Infection prevention Interleukin-4 Intestines Laboratories Lead Lipids Liver Macaca fascicularis Measures Metabolic Modeling Monkeypox Monkeys Morbidity - disease rate Nucleosides Oral Organ Transplantation Orthohepadnavirus Orthopoxvirus Persons Pharmaceutical Chemistry Pharmaceutical Preparations Polyomavirus Poxviridae Poxviridae Infections Prevention Primates Prophylactic treatment Public Health Role Self-Administered Small Intestines Smallpox Smallpox Vaccine Smallpox Viruses Structure Testing Time Toxic effect Toxicity Tests Vaccinated Vaccination Vaccines Vaccinia Variant Viral Virus Virus Diseases Work absorption analog analytical method biodefense comparative efficacy dosage gastrointestinal improved in vivo inhibitor/antagonist innovation mortality oxidation phosphonate prevent skin disorder treatment duration treatment effect viral DNA

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposal is to evaluate potent new drugs for smallpox and vaccination complications. Smallpox, caused by the variola virus, is an important bioterrorist threat and although sufficient smallpox vaccine is available, there are a number of reasons to have an FDA approved, orally active antiviral drug which can be self administered. Up to 40 million persons are not good candidates for vaccination including those with AIDS, immunosuppression, organ transplants, cancer chemotherapy and common skin diseases. Exposed persons who are vaccinated too late after exposure may not gain immune protection in time to prevent infection and death. In addition, IL-4 variants of poxviruses have been described which can bypass immune protection of vaccines. For these reasons, an orally active drug for the prevention and treatment of smallpox would be highly desirable. In 1999, our laboratory discovered an orally active lipid ester of cidofovir which shows excellent activity in four animal models of poxvirus disease, both preventing disease and treating disease after infection and this analog is currently in development. Issues have arisen in development which must be overcome if FDA approval is to be obtained. These include toxicity to the GI tract and fast degradation in pivotal monkey models of poxvirus disease which are required for FDA approval under the Animal Equivalence Rule. Recently, we developed a innovative medicinal chemistry paradigm to stabilize poxvirus antivirals like hexadecyloxypropyl-cidofovir (CMX001) against rapid degradation in primates. In this project, we propose in depth evaluation of these new drugs in poxvirus infected cells and in lethal animal models of orthopoxvirus disease. We will carry out studies to evaluate the effects of chemical structure on their metabolic stability in monkey liver S9 fractions, gastrointestinal transit and toxicity and test them in lethal animal models of poxvirus disease including, ectromelia, cowpox and vaccinia. Conventional poxvirus antivirals and the new metabolically stable analogs will be compared in an oral monkey pharmacokinetics proof of concept study. Several of these new compounds have a broad spectrum of antiviral activity against other viruses including the human immunodeficiency virus, herpes group viruses, hepatitis B and C viruses and polyoma virus and may find clinical uses for other diseases in addition to smallpox We have discovered several new antiviral drugs for the prevention and treatment of smallpox, an important threat agent for bioterrorism. In this project, we will select the most effective compounds and test them for metabolic stability in monkeys, the required model for FDA approval, and test their activity in lethal animal models of poxvirus disease. This project could lead to safer and more effective drugs for biodefense against smallpox as well as for civilian viral diseases because the agents are broad spectrum antivirals which are active against many viral infections.

描述（由申请人提供）：本提案的目的是评估治疗天花和疫苗接种并发症的有效新药。由天花病毒引起的天花是一种重要的生物恐怖威胁，尽管有足够的天花疫苗可供使用，但有很多理由需要 FDA 批准、可以自行注射的口服活性抗病毒药物。多达 4000 万人不适合接种疫苗，其中包括艾滋病患者、免疫抑制患者、器官移植患者、癌症化疗患者和常见皮肤病患者。暴露后接种疫苗太晚的暴露者可能无法及时获得免疫保护以预防感染和死亡。此外，痘病毒的 IL-4 变体已被描述可以绕过疫苗的免疫保护。由于这些原因，非常需要一种用于预防和治疗天花的口服活性药物。 1999年，我们实验室发现了一种口服活性的西多福韦脂酯，它在四种痘病毒疾病动物模型中显示出优异的活性，既可以预防疾病，也可以治疗感染后的疾病，该类似物目前正在开发中。如果要获得 FDA 的批准，开发过程中出现了一些问题，必须克服这些问题。这些包括对胃肠道的毒性和痘病毒疾病关键猴模型的快速降解，这是 FDA 根据动物等效规则批准的要求。最近，我们开发了一种创新的药物化学范例，以稳定十六烷氧基丙基西多福韦 (CMX001) 等痘病毒抗病毒药物，防止其在灵长类动物中快速降解。在这个项目中，我们建议在痘病毒感染的细胞和正痘病毒疾病的致死动物模型中深入评估这些新药。我们将开展研究，评估化学结构对其在猴肝 S9 组分中的代谢稳定性、胃肠道运输和毒性的影响，并在痘病毒疾病（包括痘痘、牛痘和牛痘）的致死动物模型中进行测试。传统的痘病毒抗病毒药物和新的代谢稳定类似物将在口服猴药代动力学概念验证研究中进行比较。其中几种新化合物对其他病毒具有广谱抗病毒活性，包括人类免疫缺陷病毒、疱疹病毒、乙型和丙型肝炎病毒以及多瘤病毒，并且可能在除天花之外的其他疾病中找到临床用途我们发现了几种用于预防和治疗天花的新抗病毒药物，天花是生物恐怖主义的重要威胁因素。在这个项目中，我们将选择最有效的化合物并测试它们在猴子（FDA 批准所需的模型）中的代谢稳定性，并测试它们在痘病毒疾病的致死动物模型中的活性。该项目可能会产生更安全、更有效的药物，用于生物防御天花以及民用病毒性疾病，因为这些药物是广谱抗病毒药物，对许多病毒感染具有活性。