Improving Absorption and Targeting of Antiviral Drugs

描述(由申请人提供)：由于最近发生的令人不安的事件预示着紧迫感的增加，NIAID的目标是天花(天花)的治疗、疫苗、佐剂/免疫刺激剂和诊断的研究和开发。TSRL获得了第一阶段SBIR，以探索前药战略，以增加潜在抗天花药物的口服可获得性。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战略将促进更有效的抗病毒药物的开发，并减少不良后果，如药物毒性、患者依从性差和成本高昂。这个生物防御项目的长期目标是通过设计针对在人体肠道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，在体内将吸收的药物从前药形式释放出来，从而改善有效但吸收不足的抗痘药物的口服吸收。在这个项目中，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)建立了合作关系。第一阶段项目的工作主要集中在环状西多福韦(CHPMPC)的前体药物上，这是一种广谱抗病毒化合物，对天花和其他正痘病毒具有很强的活性，但由于其口服生物利用度很低，在天花流行中的价值有限。我们证明了由McKenna教授的实验室首次发现的cHPMPC的二肽前体药物具有巨大的口服给药潜力。动物口服生物利用度模型的结果表明，第一代二肽前药的吸收比母药cHPMPC大一个数量级，并且很大一部分被吸收的前药在体内被转化为药物。在这个第二阶段的SBIR方案中，我们设计了一种合成策略和SAR计划，以优化这一新类别前药的生物利用度。我们已经形成了一个由研究人员和专家组成的合作网络，这将使我们能够系统地测试不同的新型cHPMPC双肽结合物的稳定性、转运、药物口服生物利用度和在公认的动物模型中的疗效。显示最佳口服吸收和疗效的化合物将按照GMP要求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口服药物。在这个项目中取得成功所需的专业知识将由TSRL公司的人员与密歇根大学抗病毒药物领域的专家John Drach博士和南加州大学的Charles McKenna博士合作提供，后者在含磷化合物的有机和药物化学方面经验丰富。

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.