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

  • J Med Chem. 2014 Mar 13;57(5):1914-31. doi: 10.1021/jm401329s.
Francisco X Talamas  1 ,  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 Nájera ,  Jaehyeon Park ,  Aruna Railkar ,  Sonal Rajyaguru ,  Michael Sangi ,  Ryan C Schoenfeld ,  Leanna R Staben ,  Yunchou Tan ,  Joshua P Taygerly ,  Armando G Villaseñor ,  Paul E Weller
Affiliations
  • 1. Pharma Research and Early Development, Hoffmann-La Roche Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
PMID: 24195700 DOI: 10.1021/jm401329s
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.

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