Discovery of N-[4-[6-tert-Butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]phenyl]methanesulfonamide (RG7109), a Potent Inhibitor of the Hepatitis C Virus NS5B Polym

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• 作者：Francisco X. Talamas ; Sarah C. Abbot ; Shalini Anand ; Ken A. Brameld ; David S. Carter ; Jun Chen ; Dana Davis ; Javier de Vicente ; Amy D. Fung ; Leyi Gong ; Seth F. Harris ; Petra Inbar ; Sharada S. Labadie ; Eun K. Lee ; Remy Lemoine ; Sophie Le Pogam ; Vincent Leveque ; Jim Li ; Joel McIntosh ; Isabel N谩jera ; Jaehyeon Park ; Aruna Railkar ; Sonal Rajyaguru ; Michael Sangi ; Ryan C. Schoenfeld ; Leanna R. Staben ; Yunchou Tan ; Joshua P. Taygerly ; Armando G. Villase帽or ; Paul E. Weller
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：1914-1931
• 全文大小：583K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.