Improving Absorption and Targeting of Antiviral Drugs

改善抗病毒药物的吸收和靶向

• 批准号: 7666289
• 负责人: John M Hilfinger
• 金额: $ 100万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666289
• 关键词: Acute; Amidohydrolases; Animal Model; Animals; Antiviral Agents; Area; Biological; Biological Assay; Biological Availability; Biological Products; California; Canis familiaris; Cell Culture Techniques; Cessation of life; Cidofovir; Cities; Clinical Trials; Collaborations; Contracts; Cowpox virus; Data; Development; Diagnostic; Dipeptides; Disease; Dose; Drug Kinetics; Drug Transport; Drug toxicity; Epidemic; Evaluation; Event; Floxuridine; Future; Generations; Goals; Grant; Human; Human Cell Line; Human Resources; Hydrolysis; Immunologic Adjuvants; In Situ; Intestinal Absorption; Intestines; Laboratories; Lead; Libraries; Link; Maximum Tolerated Dose; Metabolism; Michigan; Modeling; Modification; National Institute of Allergy and Infectious Disease; Oral; Outcome; Parents; Pattern; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphorous; Positioning Attribute; Poxviridae; Prodrugs; Property; Rattus; Relative (related person); Research Personnel; Series; Small Business Innovation Research Grant; Smallpox; Specialist; Structure; System; Targeted Research; Testing; Toxic effect; Toxicity Tests; Toxicology; Universities; Vaccine Adjuvant; Vaccinia; Virus; Virus Diseases; Work; absorption; amidase; base; biodefense; compliance behavior; cost; cyclic-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; cytotoxicity; design; drug candidate; esterase; experience; improved; in vivo; in vivo Model; novel; research and development; research clinical testing; stability testing; therapeutic vaccine; uptake; working group

DESCRIPTION (provided by applicant): With recent unsettling events foreshadowing an increased sense of urgency, NIAID has targeted research and development of therapeutics, vaccines, adjuvants/immunostimulants, and diagnostics for smallpox (variola). TSRL was granted a Phase I SBIR to explore prodrug strategies to increase the oral availability of potential anti-smallpox drugs. Strategies that can improve the oral bioavailability of approved drugs as well as potential drug candidates will facilitate the development of more effective antiviral agents and reduce undesirable outcomes such as drug toxicity, poor patient compliance, and high costs. The long-term goal of this project for biodefense is to improve the oral absorption of potent, but poorly absorbed anti-pox agents by designing prodrugs targeted to transporters expressed in human intestine and able to be activated by endogenous esterases or amidases that release the absorbed drug in vivo from its prodrug form. For this project, we established collaborations with Prof. Charles McKenna (prodrug design and synthesis) at the University of Southern California and Prof. John Drach (virological studies) at the University of Michigan. The work in the Phase I project focused chiefly on prodrugs of cyclic cidofovir (cHPMPC), a broad spectrum antiviral compound with potent activity against variola and other orthopox viruses, but of limited value in a smallpox epidemic due to its very low oral bioavailability. We demonstrated that dipeptide prodrugs of cHPMPC, which were first discovered in Prof. McKenna's laboratory, have great potential for oral delivery. Our results from an animal oral bioavailability model indicate that absorption of the first generation of dipeptide prodrugs is up to an order of magnitude greater than that of the parent drug cHPMPC, and that a significant fraction of the absorbed prodrug is converted to drug in vivo. In this Phase II SBIR proposal, we have devised a synthetic strategy and SAR plan to optimize the bioavailability of this new class of prodrug. We have formed a collaborative network of researchers and specialists that will allow us to systematically test a diverse library of novel cHPMPC dipeptide conjugates for stability, transport, drug oral bioavailability, and efficacy in accepted animal models. The compound or compounds showing the best oral absorption and efficacy will be manufactured following GMP requirements and tested for toxicity. The combined portfolio of pharmacokinetic, metabolism, manufacturing and toxicological data will be used in support of an IND and future clinical testing. The long term objective of this project is to make new oral drugs 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, and Dr. Charles Mckenna at the University of Southern California, who is well experienced at organic and medicinal chemistry of phosphorous containing compounds.

描述（由申请人提供）：最近发生的令人不安的事件预示着紧迫感的增加，NIAID 有针对性地研究和开发天花（天花）的治疗方法、疫苗、佐剂/免疫刺激剂和诊断方法。 TSRL 获得了 I 期 SBIR 批准，以探索前药策略，以提高潜在抗天花药物的口服可用性。能够提高已批准药物以及潜在候选药物的口服生物利用度的策略将有助于开发更有效的抗病毒药物，并减少药物毒性、患者依从性差和高成本等不良后果。该生物防御项目的长期目标是通过设计针对人肠道中表达的转运蛋白的前药，并能够被内源性酯酶或酰胺酶激活，释放吸收的抗痘药物，从而改善有效但吸收不良的抗痘药物的口服吸收。药物在体内以其前药形式存在。对于这个项目，我们与南加州大学的 Charles McKenna 教授（前药设计和合成）和密歇根大学的 John Drach 教授（病毒学研究）建立了合作。第一阶段项目的工作主要集中在环西多福韦（cHPMPC）的前药上，这是一种广谱抗病毒化合物，对天花和其他正痘病毒具有有效的活性，但由于其口服生物利用度非常低，因此在天花流行中的价值有限。我们证明，cHPMPC 的二肽前药是由 McKenna 教授实验室首次发现的，具有口服给药的巨大潜力。我们的动物口服生物利用度模型结果表明，第一代二肽前药的吸收比母体药物 cHPMPC 高出一个数量级，并且吸收的前药的很大一部分在体内转化为药物。在这个 II 期 SBIR 提案中，我们设计了一个合成策略和 SAR 计划来优化这类新型前药的生物利用度。我们已经形成了一个由研究人员和专家组成的协作网络，使我们能够系统地测试各种新型 cHPMPC 二肽缀合物库的稳定性、转运、药物口服生物利用度和在公认的动物模型中的功效。显示最佳口服吸收和功效的一种或多种化合物将按照 GMP 要求进行生产并进行毒性测试。药代动力学、代谢、制造和毒理学数据的组合将用于支持 IND 和未来的临床测试。 该项目的长期目标是制造治疗天花的新型口服药物。该项目成功所需的专业知识将由 TSRL, Inc. 人员与密歇根大学抗病毒药物领域专家 John Drach 博士和南方大学 Charles Mckenna 博士合作提供加利福尼亚州，在含磷化合物的有机化学和药物化学方面拥有丰富的经验。