Division of Discovery Chemistry Service, WuXi AppTec Co. Ltd, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
Bioorg Med Chem. 2011 Aug 15;19(16):4690-703. doi: 10.1016/j.bmc.2011.06.079. Epub 2011 Jul 1.
Hepatitis C virus (HCV) is a major health burden, with an estimated 170 million chronically infected individuals worldwide, and a leading cause of liver transplantation. Patients are at increased risk of developing liver cirrhosis, hepatocellular carcinoma and even liver failure. In the past two decades, several approaches have been adopted to inhibit non-structural viral proteins. The RNA-dependent RNA polymerase (NS5B) of HCV is one of the attractive validated targets for development of new drugs to block HCV infection. In this review, we report the recent progress made towards identifying and developing benzothiadiazines as HCV NS5B polymerase inhibitors. The substituted benzothiadiazine class was identified by HTS in 2002 as an NS5B inhibitor. Further optimization and modification of the core has improved the potency and pharmacokinetic properties of substituted benzothiadiazines. Research on palm site-binding benzothiadiazine analogs and related derivatives and analogs is discussed in this article.
丙型肝炎病毒 (HCV) 是一个重大的健康负担，全球估计有 1.7 亿慢性感染个体，是肝移植的主要原因。患者发生肝硬化、肝细胞癌甚至肝衰竭的风险增加。在过去的二十年中，已经采用了几种方法来抑制非结构病毒蛋白。丙型肝炎病毒的 RNA 依赖性 RNA 聚合酶 (NS5B) 是开发新药物以阻断丙型肝炎病毒感染的有吸引力的已验证靶标之一。在这篇综述中，我们报告了在鉴定和开发苯并噻二嗪作为丙型肝炎病毒 NS5B 聚合酶抑制剂方面取得的最新进展。2002 年，高通量筛选 (HTS) 发现取代的苯并噻二嗪类化合物是 NS5B 抑制剂。进一步优化和修饰核心提高了取代苯并噻二嗪的效力和药代动力学特性。本文讨论了 palm 位点结合苯并噻二嗪类似物及相关衍生物和类似物的研究。
