title: 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.
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.
authors.affiliation: Pharma Research and Early Development, Hoffmann-La Roche Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Talamas
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Abbot
authors.forename: Shalini
authors.initials: S
authors.lastname: Anand
authors.forename: Ken A
authors.initials: KA
authors.lastname: Brameld
authors.forename: David S
authors.initials: DS
authors.lastname: Carter
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Dana
authors.initials: D
authors.lastname: Davis
authors.forename: Javier
authors.initials: J
authors.lastname: de Vicente
authors.forename: Amy D
authors.initials: AD
authors.lastname: Fung
authors.forename: Leyi
authors.initials: L
authors.lastname: Gong
authors.forename: Seth F
authors.initials: SF
authors.lastname: Harris
authors.forename: Petra
authors.initials: P
authors.lastname: Inbar
authors.forename: Sharada S
authors.initials: SS
authors.lastname: Labadie
authors.forename: Eun K
authors.initials: EK
authors.lastname: Lee
authors.forename: Remy
authors.initials: R
authors.lastname: Lemoine
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Pogam
authors.forename: Vincent
authors.initials: V
authors.lastname: Leveque
authors.forename: Jim
authors.initials: J
authors.lastname: Li
authors.forename: Joel
authors.initials: J
authors.lastname: McIntosh
authors.forename: Isabel
authors.initials: I
authors.lastname: Nájera
authors.forename: Jaehyeon
authors.initials: J
authors.lastname: Park
authors.forename: Aruna
authors.initials: A
authors.lastname: Railkar
authors.forename: Sonal
authors.initials: S
authors.lastname: Rajyaguru
authors.forename: Michael
authors.initials: M
authors.lastname: Sangi
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Schoenfeld
authors.forename: Leanna R
authors.initials: LR
authors.lastname: Staben
authors.forename: Yunchou
authors.initials: Y
authors.lastname: Tan
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Taygerly
authors.forename: Armando G
authors.initials: AG
authors.lastname: Villaseñor
authors.forename: Paul E
authors.initials: PE
authors.lastname: Weller
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D011804:Quinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011804:Quinolines; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C588341:N-(4-(6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl)phenyl)methanesulfonamide; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase