title: Recent advances in drug discovery of benzothiadiazine and related analogs as HCV NS5B polymerase inhibitors.
abstract: 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.
authors.affiliation: Division of Discovery Chemistry Service, WuXi AppTec Co. Ltd, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China. debasis_das@wuxiapptec.com
authors.forename: Debasis
authors.initials: D
authors.lastname: Das
authors.forename: Jian
authors.initials: J
authors.lastname: Hong
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Chen
authors.forename: Guangyi
authors.initials: G
authors.lastname: Wang
authors.forename: Leonid
authors.initials: L
authors.lastname: Beigelman
authors.forename: Scott D
authors.initials: SD
authors.lastname: Seiwert
authors.forename: Brad O
authors.initials: BO
authors.lastname: Buckman
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001581:Benzothiadiazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D058990:Molecular Targeted Therapy; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase