Vidarabine Prodrugs as Anti-Pox Virus Agents

描述（由申请人提供）：民用生物防御工作组已将天花确定为最严重的生物制剂之一，可能导致大量疾病和死亡，使一个城市或地区瘫痪。国家过敏和传染病研究所的目标是研究和开发治疗方法、疫苗、佐剂/免疫刺激剂以及天花和其他病毒性疾病的诊断方法。在TSRL， Inc.，我们一直在开发一种改进抗病毒药物的前药物策略。虽然最近在这一领域的研究为治疗这些疾病的候选药物数量提供了适度的增加，但许多潜在的抗病毒药物由于其极低的口服生物利用度而被排除在临床应用之外。能够提高已批准药物和潜在候选药物的口服生物利用度的策略将促进高效抗病毒药物的开发，并减少与当前治疗相关的不良特性，如药物毒性、患者依从性差和高成本。前药方法最近已成为一种有效的策略，最近抗病毒前药如阿德福韦酯、泛环洛韦、替诺福韦二氧proxil、valacyclovir和缬更昔洛韦的成功证明了这一点。该项目的长期目标是改善吸收不良的抗病毒药物的口服吸收，并增强其对特定组织的递送，从而提高疗效。该建议的中心假设是，口服吸收不良和快速代谢的抗痘病毒药物（阿糖腺苷）可以改善，新的前药可以特异性靶向感兴趣的细胞。我们对阿糖腺苷的前药非常感兴趣，因为我们最近发现，阿糖腺苷对牛痘病毒和牛痘病毒的活性是西多福韦的3到5倍，西多福韦是目前唯一可用于治疗痘病毒感染的药物。此外，通过与腺苷脱氨酶抑制剂结合，我们能够将阿糖腺苷抗这些病毒的活性提高约10倍，从而提供了比西多福韦显著的优势。在这个项目中使用的方法将是设计和合成针对人类肠道中表达的转运蛋白的前药，也针对特异性地将前药片段切割到母体化合物的“激活”酶。此外，阿糖腺苷前药的设计将重点关注抑制腺苷脱氨酶对阿糖腺苷代谢的化合物，以进一步提高其活性。最近对大鼠十二指肠注射原型氨基酸前体药物的初步研究证实了这一方法。与阿糖腺苷本身相比，服用前药时阿糖腺苷的血浆水平高出10倍。值得注意的是，与人类相比，阿糖腺苷在啮齿动物中的代谢更广泛，因此我们建议使用人类细胞系和靶向人类转运蛋白是至关重要的。TSRL, Inc.的人员将与密歇根大学抗病毒药物领域的专家John Drach博士合作，提供扩大和成功开展这些努力所需的专业知识，他是阿糖腺苷代谢和作用方式的先驱研究者。

DESCRIPTION (provided by applicant): The Working Group for Civilian Biodefense has identified smallpox as one of the most serious biological agents that could cause disease and deaths in sufficient numbers to cripple a city or region. The National Institute of Allergy and Infectious Disease has targeted research and development of therapeutics, vaccines, adjuvants/immunostimulants, and diagnostics for small pox and other viral diseases. At TSRL, Inc., we have been developing a prodrug strategy for the improvement of antiviral drugs. While recent research in this area has provided a modest increase in the number of drug candidates for treatment of these diseases, many potential antiviral agents are precluded from clinical use due to their extremely low oral bioavailability. Strategies that can improve the oral bioavailability of approved drugs as well as potential drug candidates will facilitate the development of highly effective antiviral agents and reduce undesirable properties such as drug toxicity, poor patient compliance, and high costs associated with current therapy. The prodrug approach recently has been an effective strategy as demonstrated by the recent success of antiviral prodrugs such as adefovir dipivoxil, famciclovir, tenofovir disoproxil, valacyclovir, and valganciclovir. The long-term goal of this project is to improve the oral absorption of poorly absorbed antiviral drugs and to enhance their delivery to specific tissues, thus improving efficacy. The central hypothesis of this proposal is that oral absorption of a poorly absorbed and rapidly metabolized drug that is active against pox viruses (vidarabine) can be improved and new prodrugs can be specifically targeted to the cells of interest. We have become very enthusiastic about prodrugs of vidarabine because of our recent discovery that vidarabine is 3 to 5-fold more active against vaccinia and cow pox viruses than is cidofovir, the only drug currently available to treat pox virus infections. Furthermore, we were able to increase the activity of vidarabine against these viruses approximately 10-fold by combination with an adenosine deaminase inhibitor thereby providing highly significant superiority to cidofovir. The approach used in this project will be the design and synthesis of prodrugs targeted to transporters expressed in human intestine and also targeted to "activation" enzymes that specifically cleave the prodrug moiety to its parent compound. In addition, the design of vidarabine prodrugs will focus on compounds that inhibit the metabolism of vidarabine by adenosine deaminase to further enhance its activity. Recent preliminary studies involving rat duodenal injection of prototype amino acid prodrugs have validated this approach. Plasma levels of vidarabine were >10-fold greater when the prodrug was dosed compared to administration of vidarabine itself. It should be noted that vidarabine is metabolized more extensively in rodents compared to humans thus our proposed use of human cell lines and targeting human transporters is critical. The expertise needed to expand and succeed in these endeavors will be provided by personnel at TSRL, Inc. in collaboration with Dr. John Drach, an expert in the area of antiviral drugs at the University of Michigan, who was a pioneer investigator of vidarabine metabolism and mode of action. The long term objective of this project is to make new oral drug formulations for the treatment of small pox. The expertise needed to succeed in this project will be provided by personnel at TSRL, Inc. in collaboration with Dr. John Drach, an expert in the area of antiviral drugs at the University of Michigan.