Orally Active Nucleoside Phosphonates for Hepatitis C Virus

丙型肝炎病毒(HCV)感染了大约400万美国人和1.7亿人 以全球为基础。尽管过去两年与血液制品相关的传播大幅减少 几十年来，特别是在资源丰富的环境中，注射吸毒者之间的传播仍在继续，而且有 越来越多的证据表明，在从事高危性行为的个人中传播。此外， 由于该病毒的大部分发病率与慢性肝病有关，需要20年或更长时间才能发展起来， 无论如何，至少在未来十年内，美国丙型肝炎病毒相关的发病率和死亡率都将增加 当前的传输速率。在过去的10年里，在治疗方面有了稳步的进步。 随着聚乙二醇化干扰素(聚乙二醇化干扰素)-利巴韦林治疗方案的演变而进行的选择。尽管如此 在美国最常见的丙型肝炎病毒(基因1)中，只有大约50%的人可以 耐受整个疗程，对以聚乙二醇化干扰素为基础的治疗完全有反应。的禁忌症和毒性 当前方案的组成部分排除了许多候选治疗方案开始或完成完整的 并表明干扰素疗法不太可能有实质性的进一步改善。 在过去的三年里，小分子的发展取得了越来越大的进展。 丙型肝炎病毒NS3/NS4a蛋白酶和NS5B聚合酶的抑制剂。针对每个分子的化合物 塔吉特已经清楚地证明了体内的概念验证，与聚乙二醇干扰素的联合研究正在进行中。 丙型肝炎病毒与艾滋病毒有两个共同的关键特性：高复制率和低复制保真度，这使得它高度 很可能所有有效的小分子疗法都需要使用针对几个 分子靶标。 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腔治疗 针对丙型肝炎病毒聚合酶的活性核苷膦化合物。我们已经创建了一系列 烷氧基核苷膦酸衍生物，可显著增强抗病毒活性和 母体核苷的药代动力学特性。使用我们在以下领域成功采用的方法 针对HIV、痘病毒和疱疹病毒的药物发现我们建议对其进行系统评估 丙型肝炎病毒感染的设定方法，认为丙型肝炎病毒治疗的下一个实质性进展 可能需要开发无干扰素的疗法，这将需要有更多的 比目前手中的更多的小分子丙型肝炎病毒抑制剂。

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.