Q1 · MEDICINE
Article
Author: Gong, Leyi ; Staben, Leanna R. ; Park, Jaehyeon ; Leveque, Vincent ; Le Pogam, Sophie ; de Vicente, Javier ; Chen, Jun ; Tan, Yunchou ; Talamas, Francisco X. ; Railkar, Aruna ; Inbar, Petra ; Carter, David S. ; Labadie, Sharada S. ; Weller, Paul E. ; Lee, Eun K. ; Lemoine, Remy ; Harris, Seth F. ; Abbot, Sarah C. ; Fung, Amy D. ; Davis, Dana ; Schoenfeld, Ryan C. ; McIntosh, Joel ; Rajyaguru, Sonal ; Sangi, Michael ; Li, Jim ; Taygerly, Joshua P. ; Anand, Shalini ; Villaseñor, Armando G. ; Brameld, Ken A. ; Nájera, Isabel
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.