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 polymerase.
Talamas, F.X., Abbot, S.C., Anand, S., Brameld, K.A., Carter, D.S., Chen, J., Davis, D., de Vicente, J., Fung, A.D., Gong, L., Harris, S.F., Inbar, P., Labadie, S.S., Lee, E.K., Lemoine, R., Le Pogam, S., Leveque, V., Li, J., McIntosh, J., Najera, I., Park, J., Railkar, A., Rajyaguru, S., Sangi, M., Schoenfeld, R.C., Staben, L.R., Tan, Y., Taygerly, J.P., Villasenor, A.G., Weller, P.E.(2014) J Med Chem 57: 1914-1931
- PubMed: 24195700 
- DOI: https://doi.org/10.1021/jm401329s
- Primary Citation of Related Structures:  
4MIA, 4MIB - PubMed Abstract: 
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.
Organizational Affiliation: 
Pharma Research and Early Development, Hoffmann-La Roche Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.