1. 2-(3-Thienyl)-5,6-dihydroxypyrimidine-4-carboxylic acids as inhibitors of HCV NS5B RdRp
- Author
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Frank Narjes, Barbara Pacini, Laura Pacini, Salvatore Avolio, Giovanni Migliaccio, Licia Tomei, Caterina Ercolani, Uwe Koch, and Steven Harper
- Subjects
Stereochemistry ,Hepatitis C virus ,Carboxylic acid ,Clinical Biochemistry ,Carboxylic Acids ,Pharmaceutical Science ,Hepacivirus ,Viral Nonstructural Proteins ,Virus Replication ,medicine.disease_cause ,Antiviral Agents ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Catalytic Domain ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Computer Simulation ,Enzyme Inhibitors ,Molecular Biology ,NS5B ,chemistry.chemical_classification ,Sulfonyl ,biology ,Organic Chemistry ,virus diseases ,Active site ,RNA-Dependent RNA Polymerase ,digestive system diseases ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
A series of 2-(3-thienyl)-5,6-dihydroxypyrimidine-4-carboxylic acid inhibitors of the hepatitis C virus (HCV) NS5B polymerase enzyme are reported. Sulfonyl urea substituted analogs in this series proved to be the most potent active site non-nucleoside inhibitors of NS5B reported to date. These compounds had low nanomolar enzyme inhibition across HCV genotypes 1-3 and showed single digit micromolar inhibition in the HCV replicon assay. This improved cell-based activity allowed the binding mode of these compounds to be probed by selection of resistant mutations against compound 21. The results generated are in broad agreement with the previously proposed binding model for this compound class.
- Published
- 2009