ANTI-POXVIRUS NUCLEOSIDES:SYNTHESIS AND EVALUATION

抗痘病毒核苷：合成与评价

• 批准号: 6555626
• 负责人: KYOICHI A WATANABE
• 金额: $ 21.42万
• 依托单位: PHARMASSET, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6555626
• 关键词: Poxviridae; Poxviridae disease; antiviral agents; bioterrorism /chemical warfare; chemical synthesis; cidofovir; clinical research; cytomegalovirus; drug design /synthesis /production; human tissue; immunologic substance development /preparation; immunopharmacology; laboratory mouse; plaque assay; pyrimidine nucleosides; tissue /cell culture; vaccinia virus; virus cytopathogenic effect

DESCRIPTION (provided by applicant): There are currently no approved antiviral therapies that could be rapidly deployed in the event of a bioterrorism attack using a poxvirus or the unexpected spread of an indigenous agent like monkey poxvirus to other parts of the world. Initial efforts in drug development for poxvirus infections have focused on the identification of compounds that are already approved for use in some other infection. The best candidate currently is cidofovir, which is approved for treatment of certain cytomegalovirus infections, is a potent inhibitor of poxvirus replication in vitro and has been shown to be very effective against both vaccinia virus (VV) and cowpox virus (CV) infections in animal model infections. Its nephrotoxicity and poor oral availability, however, limit its usefulness. Therefore, there is a continued need to develop new and better modes of therapy for Poxvirus Infection. The specific aims of this SBIR Phase I project are to: 1) Synthesize new series of pyrimidine nucleosides (about 30), which are designed on the basis of rationale described in the sections B. C and D; 2) Evaluate the antiviral efficacy of these nucleosides against VV and CV by plaque reduction assay in tissue culture in collaboration with Prof. Earl R. Kern of the University of Alabama at Birmingham; and 3) Determine the efficacy of lead compounds in animal model infections of VV and CV, also in collaboration with Professor Kern. In addition, the in vitro and in vivo toxicity of the compounds will be determined in-house as well as in collaboration with Dr. Kern. We plan to synthesize 31 novel pyrimidine nucleosides for antiviral evaluation in tissue culture systems. We estimate, based on our preliminary results, that three of four compounds will have sufficient activity in the animal model infections and select one or two candidates for further development in Phase II. In Phase II, we plan to further investigate those active nucleosides selected in Phase I for their detailed preclinical pharmacological and toxicological features in small animals and dogs for IND application.

描述（由申请人提供）：目前没有批准的抗病毒疗法可以在使用痘病毒的生物恐怖主义袭击或本土病原体（如猴痘病毒）意外传播到世界其他地区的情况下快速部署。痘病毒感染药物开发的最初努力集中在鉴定已经被批准用于其他感染的化合物上。目前最好的候选药物是西多福韦，它被批准用于治疗某些巨细胞病毒感染，是一种有效的痘病毒体外复制抑制剂，并已被证明是非常有效的对牛痘病毒（VV）和牛痘病毒（CV）感染的动物模型感染。然而，其肾毒性和口服可用性差限制了其用途。因此，持续需要开发新的和更好的痘病毒感染的治疗模式。本SBIR第一阶段项目的具体目标是：1）合成新系列的嘧啶核苷（约30个），这些嘧啶核苷是根据B部分中描述的原理设计的。C和D; 2）与Earl R.教授合作，通过组织培养中的空斑减少试验评估这些核苷对VV和CV的抗病毒功效。亚拉巴马大学伯明翰分校的克恩教授;以及3）确定先导化合物在VV和CV动物模型感染中的功效，也是与克恩教授合作。此外，将在内部以及与克恩博士合作确定化合物的体外和体内毒性。我们计划合成31种新型嘧啶核苷，用于组织培养系统中的抗病毒评价。根据我们的初步结果，我们估计四种化合物中的三种将在动物模型感染中具有足够的活性，并选择一种或两种候选化合物用于II期的进一步开发。在II期，我们计划进一步研究I期选择的活性核苷在小动物和犬中的详细临床前药理学和毒理学特征，以供IND申请。