Vidarabine Prodrugs as Anti-Pox Virus Agents

作为抗痘病毒剂的阿糖腺苷前药

• 批准号: 7271529
• 负责人: John M Hilfinger
• 金额: $ 29.78万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271529
• 关键词: Adenosine Deaminase Inhibitor; Amino Acids; Animal Model; Animal Testing; Antiviral Agents; Arasena-A; Area; Biological Availability; Biological Products; Cells; Cessation of life; Characteristics; Cidofovir; Cities; Cleaved cell; Clinical; Collaborations; Cowpox virus; Deamination; Development; Diagnostic; Disease; Dose; Drug Formulations; Drug toxicity; Enzyme Activation; Enzymes; Evaluation; Famciclovir; Goals; Human; Human Cell Line; Human Resources; Hydrolysis; Immunologic Adjuvants; Injection of therapeutic agent; Intestines; Mediating; Metabolism; Michigan; Mus; National Institute of Allergy and Infectious Disease; Numbers; Oral; Outcome; Parents; Permeability; Pharmaceutical Preparations; Phase; Plasma; Poxviridae; Prodrugs; Property; Rattus; Research; Research Personnel; Resistance; Rodent; Role; Services; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Smallpox; Targeted Research; Techniques; Testing; Therapeutic Agents; Tissues; United States National Institutes of Health; Universities; Vaccine Adjuvant; Vaccinia; Valganciclovir; Vidarabine; Virus; Virus Diseases; Work; absorption; adefovir dipivoxil; adenosine deaminase; analog; biodefense; compliance behavior; cost; cytotoxicity; design; drug metabolism; improved; inhibitor/antagonist; interest; pre-clinical; prototype; research and development; success; tenofovir disoproxil; therapeutic vaccine; uptake; valacyclovir

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.

描述（由申请人提供）：民用生物防御工作组已经确定天花是最严重的生物制剂之一，可能导致疾病和死亡，足以削弱一个城市或地区。国家过敏和传染病研究所针对天花和其他病毒性疾病的治疗、疫苗、佐剂/免疫刺激剂和诊断进行了研究和开发。在TSRL公司，我们一直在开发一种前体药物策略，以改进抗病毒药物。虽然最近在这一领域的研究已经提供了用于治疗这些疾病的候选药物数量的适度增加，但许多潜在的抗病毒剂由于其极低的口服生物利用度而被排除在临床使用之外。可以提高批准药物以及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剂的开发，并减少不期望的性质，例如药物毒性、患者依从性差以及与当前治疗相关的高成本。前药方法最近已成为一种有效的策略，如最近成功的抗病毒前药，如阿德福韦酯，泛昔洛韦，替诺福韦酯，伐昔洛韦和缬更昔洛韦。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，并增强其向特定组织的输送，从而提高疗效。该提议的中心假设是，可以改善对痘病毒具有活性的吸收不良和快速代谢的药物（阿糖腺苷）的口服吸收，并且新的前药可以特异性地靶向感兴趣的细胞。我们对阿糖腺苷的前体药物非常感兴趣，因为我们最近发现阿糖腺苷对牛痘和牛痘病毒的活性是目前唯一可用于治疗痘病毒感染的药物西多福韦的3至5倍。此外，通过与腺苷脱氨酶抑制剂组合，我们能够将阿糖腺苷对这些病毒的活性提高约10倍，从而提供了比西多福韦更显著的优越性。该项目中使用的方法将是设计和合成靶向于人肠道中表达的转运蛋白的前药，并且还靶向于特异性地将前药部分裂解为其母体化合物的“活化”酶。此外，阿糖腺苷前药的设计将集中在抑制腺苷脱氨酶代谢阿糖腺苷的化合物，以进一步增强其活性。最近的初步研究，涉及大鼠十二指肠注射原型氨基酸前药验证了这种方法。与施用阿糖腺苷本身相比，当给予前药时，阿糖腺苷的血浆水平高>10倍。应该注意的是，与人类相比，阿糖腺苷在啮齿动物中代谢更广泛，因此我们提出的使用人类细胞系和靶向人类转运蛋白至关重要。TSRL，Inc.的人员将提供扩展和成功完成这些工作所需的专业知识。与密歇根大学抗病毒药物领域的专家John Drach博士合作，他是阿糖腺苷代谢和作用模式的先驱研究者。 该项目的长期目标是制造治疗天花的新型口服药物制剂。TSRL，Inc.的人员将提供本项目成功所需的专业知识。与密歇根大学抗病毒药物领域的专家John Drach博士合作。

项目成果

5'-O-D-valyl ara A, a potential prodrug for improving oral bioavailability of the antiviral agent vidarabine.

5-O-D-valyl ara A，一种潜在的前药，可提高抗病毒药物阿糖腺苷的口服生物利用度。

• DOI: 10.1080/15257770802581757
• 发表时间: 2009
• 期刊: Nucleosides, nucleotides & nucleic acids
• 作者: Shen,Wei;Kim,Jae-Seung;Mitchell,Stefanie;Kish,Phil;Kijek,Paul;Hilfinger,John
• 通讯作者: Hilfinger,John

Design and synthesis of vidarabine prodrugs as antiviral agents.

• DOI: 10.1016/j.bmcl.2008.12.031
• 发表时间: 2009-02-01
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Shen W;Kim JS;Kish PE;Zhang J;Mitchell S;Gentry BG;Breitenbach JM;Drach JC;Hilfinger J
• 通讯作者: Hilfinger J