Antivirals against HBV

抗乙肝病毒药物

• 批准号: 6337669
• 负责人: MICHAEL J OTTO
• 金额: $ 14.76万
• 依托单位: PHARMASSET, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6337669
• 关键词: antiviral agents; chemical structure function; chemical synthesis; combination chemotherapy; drug design /synthesis /production; drug screening /evaluation; hepatitis B; hepatitis B virus group; laboratory rat; mitochondria; nucleosides; pharmacokinetics

DESCRIPTION (provided by applicant): The global magnitude of hepatitis B viral (HBV) infection warrants development of efficient treatment strategies to combat the virus. These treatment protocols will also aid in minimizing the protracted long-term effects of HBV infection namely cirrhosis and hepatocellular carcinoma. The short-term benefits of the currently available treatment protocols are greatly offset by the emergence of the resistant phenotype in the case of Lamivudine therapy and adverse side effects in the case of alpha-interferon. As a consequence of this, the goal of maintaining low viral loads cannot be achieved. The generation of a panel of potent antivirals against HBV would be a valuable addition to existing treatments. Novel combinations of anti-HBV drugs would greatly minimize the chances of development of resistance and provide sustained reduction in viral loads. A number of 2'-fluoro-2',3'-unsaturated D- and L-nucleosides (2'-F-D4N) showed potent anti-HBV activity with no appreciable toxicity in a number of cell lines. These compounds also demonstrated anti-HIV activity in vitro. In the proposed Phase I study, these compounds will be further characterized with respect to their anti-HBV activity in combination treatments, mechanisms of action, mitochondrial toxicity, and efficacy of inhibition of HBV viral polymerase. Cross-resistance of these active nucleosides against the Lamivudine-resistant mutants will be determined. Pharmacokinetics of molecules with antiviral activity and no appreciable cellular and mitochondrial toxicity will be conducted. At the conclusion of the Phase I study, it should be possible to identify one or two best candidate molecules for detailed studies in animal models, preclinical studies and further development. Detailed studies for phase II studies which will include in vivo efficacy and sub chronic toxicology of the compounds. PROPOSED COMMERCIAL APPLICATION: There is an urgent need for therapies for the treatment and management of HBV worldwide. Limited success of the Lamivudine monotherapy and development of clinical resistance to Lamivudine have made the researchers as well as clinicians aware of the fact that alternate modalities of treatment have to be in place to tackle HBV infections successfully. Novel anti-HBV agents, hence, would have a much broader market as new combinations of drugs can be formulated.

描述（由申请人提供）：乙型肝炎病毒的全球幅度 （HBV）感染需要制定有效的治疗策略 对抗病毒。这些治疗方案还将有助于最大程度地减少 HBV感染的长期长期作用，即肝硬化和 肝细胞癌。当前可用的短期优势 抗性的出现很大程度上被治疗方案所抵消 在lamivudine治疗和不良副作用的情况下 Alpha Interferon的情况。因此，保持较低的目标 病毒负荷无法实现。一系列有效的抗病毒药 反对HBV将是现有治疗的宝贵补充。小说 抗HBV药物的组合将大大降至最低的机会 抗药性的发展并提供病毒负荷的持续减少。一个 2'-氟-2'，3'-未饱和d-和l-核苷（2'-f-d4n）的数量显示 有效的抗HBV活性在许多细胞中没有明显毒性 线。这些化合物在体外还表现出抗HIV活性。在 建议的第一阶段研究，这些化合物将进一步表征 尊重其在组合处理中的抗HBV活性，机制 作用，线粒体毒性和抑制HBV病毒的功效 聚合酶。这些活性核苷的交叉抗性 将确定耐兰氨基抗性突变体。分子的药代动力学 具有抗病毒活性，没有明显的细胞和线粒体毒性 将进行。在第一阶段研究的结论中，应该是 可以识别一个或两个最佳候选分子进行详细研究 在动物模型中，临床前研究和进一步发展。详细研究 对于II期研究，将包括体内功效和亚慢性慢性 化合物的毒理学。 拟议的商业应用： 迫切需要对全球HBV的治疗和管理进行治疗。拉米夫丁单一疗法的成功有限，并且对拉米丁的临床抵抗力的发展使研究人员以及临床医生意识到，必须成功应对HBV感染的替代治疗方式。因此，新型的抗HBV代理将拥有更广泛的市场，因为可以制定新的药物组合。