Discovery of a novel series of potent non-nucleoside inhibitors of hepatitis C virus NS5B
| Autor: | Sophie Le Pogam, Isabel Najera, Junping Zhao, Sangi Michael, Taygerly Joshua Paul Gergely, Sandra Steiner, Francisco Xavier Talamas, Javier de Vicente, Ryan Craig Schoenfeld, Amy Fung, Elbert Chin, Alfred Sui-Ting Lui, David L. Bourdet, Vincent Leveque, Seth F. Harris, Sonal Rajyaguru, Ken A. Brameld, Eun Kyung Lee, Jim Li |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Pyridones Hepatitis C virus Hepacivirus Viral Nonstructural Proteins medicine.disease_cause Antiviral Agents Article chemistry.chemical_compound Structure-Activity Relationship Dogs Pegylated interferon Cell Line Tumor Drug Discovery medicine Animals Humans Protease inhibitor (pharmacology) Molecular Targeted Therapy Enzyme Inhibitors NS5B biology Drug discovery Ribavirin Hepatitis C medicine.disease biology.organism_classification RNA-Dependent RNA Polymerase Virology Protein Structure Tertiary Rats chemistry Area Under Curve Host-Pathogen Interactions Molecular Medicine medicine.drug Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 56(20) |
| ISSN: | 1520-4804 |
| Popis: | Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Towards those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition which has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics and early safety were addressed in order to provide a clinical candidate in fluoropyridone 19. |
| Databáze: | OpenAIRE |
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