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）：民用生物福利工作组已将天花确定为最严重的生物学药物之一，可能导致疾病和死亡人数足够多，以削弱城市或地区。美国国家过敏和传染病研究所针对治疗剂，疫苗，辅助/免疫刺激剂以及小痘和其他病毒疾病的诊断。在TSRL Inc.，我们一直在制定改善抗病毒药的前药策略。尽管该领域的最新研究为治疗这些疾病的候选药物数量增加了，但由于其口服生物利用度极低，因此许多潜在的抗病毒药被排除在临床上。可以改善批准药物口服生物利用度以及潜在候选药物的策略将有助于发展高效的抗病毒药物，并降低不良特性，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。最近，这种前药方法是一种有效的策略，如抗病毒前药（如Adefovir Dipivoxil，Famciclovir，Tenofovir disoproxil，Valacyclovir和Valganciclovir）的最新成功所证明。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递送，从而提高功效。该提议的中心假设是，可以改善对痘病毒（vidarabine）活跃的吸收不良且快速代谢的药物的口服吸收，并且可以改善新的前药。我们对维达拉滨前药变得非常热情，因为我们最近发现，维达拉滨比目前唯一可用于治疗痘病毒感染的药物比vicacinia和牛痘病毒更为活跃。此外，我们能够通过与腺苷脱氨酶抑制剂结合使用约10倍的维达拉滨对这些病毒的活性，从而提供了与cidofovir的高度优势。该项目中使用的方法将是针对人类肠道转运蛋白的前药的设计和合成，也针对“激活”酶，这些酶专门将前药部分切割到其父材中。此外，维达拉滨前药的设计将集中在腺苷脱氨酶抑制维达拉滨代谢的化合物上，以进一步增强其活性。涉及大鼠十二指肠注入原型氨基酸前药的最新初步研究已经验证了这种方法。与维达拉滨本身的给药相比，对前药的给药时，维达拉滨的血浆水平大于10倍。应该注意的是，与人相比，维达拉滨在啮齿动物中更广泛地代谢，因此我们提出的人类细胞系的使用和靶向人类转运蛋白至关重要。 TSRL，Inc。的人员将与密歇根大学抗病毒药物领域的专家约翰·德拉奇（John Drach）合作，将提供扩大和成功的专业知识，该公司是维达拉宾代谢和行动模式的先驱调查员。 该项目的长期目标是为小痘的治疗制作新的口服药物制剂。 TSRL，Inc。的人员将与密歇根大学抗病毒药物领域的专家约翰·德拉奇（John Drach）合作，将提供成功完成该项目所需的专业知识。

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