Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B

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• 作者：Ryan C. Schoenfeld ; David L. Bourdet ; Ken A. Brameld ; Elbert Chin ; Javier de Vicente ; Amy Fung ; Seth F. Harris ; Eun K. Lee ; Sophie Le Pogam ; Vincent Leveque ; Jim Li ; Alfred S.-T. Lui ; Isabel Najera ; Sonal Rajyaguru ; Michael Sangi ; Sandra Steiner ; Francisco X. Talamas ; Joshua P. Taygerly ; Junping Zhao
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October 24, 2013
• 年：2013
• 卷：56
• 期：20
• 页码：8163-8182
• 全文大小：903K
• 年卷期：v.56,no.20(October 24, 2013)
• ISSN：1520-4804

文摘

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. Toward 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 that 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.