Orally Active Nucleoside Phosphonates for Hepatitis C Virus

丙型肝炎病毒（HCV）感染大约400万美国人和1.7亿人， 全球基础上。尽管在过去的两年里，与血液制品有关的传播大幅减少， 几十年来，特别是在资源充足的环境中，注射毒品使用者之间的传播仍在继续， 越来越多的证据表明，在从事高风险性行为的个人中传播。此外，委员会认为， 由于该病毒的大多数发病率与慢性肝病有关并且需要20年或更长时间才能发展， HCV相关的发病率和死亡率预计将增加在美国至少在未来十年， 当前的传输速率。在过去的10年里，在治疗方面有了稳步的改善。 随着聚乙二醇化干扰素（PEG-Ifn）-利巴韦林为基础的治疗方案的发展，尽管有这些 进展，只有大约50%的人与HCV基因型最常见的美国（基因型1）谁可以 耐受整个疗程对基于PEG-IFN治疗完全响应。禁忌症和毒性 目前方案的组成部分阻止了许多治疗候选者开始或完成完整的治疗。 治疗过程中，并表明实质性的进一步改善IFN为基础的治疗是不可能的。 在过去的3年里，在小分子药物的开发方面取得了越来越大的进展， HCV NS3/NS4a蛋白酶和NS5b聚合酶的抑制剂。针对每个分子的化合物 靶点已经清楚地证明了体内概念验证，与PEG-IFN的组合研究正在进行中。 HCV与HIV共有两个关键特性：高复制率和低复制保真度，这使得HCV在HIV感染中的作用非常重要。 可能有效的所有小分子方案将需要使用针对几个靶点的多种药物 分子靶点 正如本申请中所概述的，两个研究小组正在合作优化一系列口服 针对HCV聚合酶的活性核苷膦酸酯化合物。我们创造了一系列的 烷氧基烷基核苷膦酸酯衍生物， 母体核苷的药代动力学性质。使用我们成功运用的方法 针对HIV、痘病毒和疱疹病毒的药物发现，我们建议系统地评估这一点。 在HCV感染的背景下，认为HCV治疗的下一个实质性进展 可能需要开发无干扰素方案，这将需要大量的 比目前掌握的更大的一系列小分子HCV抑制剂。

Hepatitis C Virus (HCV) infects approximately 4 million Americans and 170 million people on a worldwide basis. Despite substantial reductions in blood product-related transmission over the past two decades, especially in resourced settings, transmission among injecting drug users continues and there is increasing evidence of transmission among individuals engaged in higher risk sexual behaviors. Furthermore, since most morbidity from the virus is related to chronic liver disease and requires 20 or more years to develop, HCV-related morbidity and mortality is projected to increase in the US for at least the next decade regardless of the current transmission rate. Over the last 10 years there have been steady improvements in therapeutic options with the evolution of pegylated interferon (PEG-Ifn)-ribavirin based treatment regimens. Despite these advances, only about 50% of those with the HCV genotype most common in the US (Genotype 1) who can tolerate a full course of therapy respond fully to PEG-Ifn based therapy. Contraindications and toxicities to components of the current regimen preclude many treatment candidates from initiating or completing a full course of therapy and suggest that substantial further improvement in Ifn-based therapies is unlikely. Over the past 3 years there has been increasing progress in the development of small molecular inhibitors of the HCV NS3/NS4a protease and the NS5b polymerase. Compounds directed at each molecular target have clearly demonstrated proof-of-concept in vivo and combination studies with PEG-Ifn are underway. HCV shares two critical properties with HIV: high replication rates and low replicative fidelity, that make it highly likely that efficacious all small molecular regimens will require the use of multiple agents directed at several molecular targets. As is outlined in this application, two research groups are collaborating to optimize a series of orally active nucleoside phosphonate compounds directed at the HCV polymerase. We have created a series of alkoxyalkyl nucleoside phosphonate derivatives that substantially enhance both the antiviral activity and the pharmacokinetic properties of parent nucleosides. Using an approach that we have successfully employed in drug discovery directed at HIV, poxviruses and herpes viruses we propose to systematically evaluate this approach in the setting of HCV infection with the view that the next substantial advance in HCV therapeutics will likely require the development of interferon-free regimens and that this will require the availability of a much larger array of small molecular HCV inhibitors than is currently in hand.