2. Academic Validation
  3. 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

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

Affiliation

  • 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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