title: Substituted imidazopyridines as potent inhibitors of HCV replication.
abstract: OBJECTIVE
  Following lead optimization, a set of substituted imidazopyridines was identified as potent and selective inhibitors of in vitro HCV replication. The particular characteristics of one of the most potent compounds in this series (5-[[3-(4-chlorophenyl)-5-isoxazolyl]methyl]-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine or GS-327073), were studied.
  
  
  METHODS
  Antiviral activity of GS-327073 was evaluated in HCV subgenomic replicons (genotypes 1b, 1a and 2a), in the JFH1 (genotype 2a) infectious system and against replicons resistant to various selective HCV inhibitors. Combination studies of GS-327073 with other selective HCV inhibitors were performed.
  
  
  RESULTS
  Fifty percent effective concentrations for inhibition of HCV subgenomic 1b replicon replication ranged between 2 and 50 nM and were 100-fold higher for HCV genotype 2a virus. The 50% cytostatic concentrations were > or = 17 microM, thus resulting in selectivity indices of > or = 340. GS-327073 retained wild-type activity against HCV replicons that were resistant to either HCV protease inhibitors or several polymerase inhibitors. GS-327073, when combined with either interferon alpha, ribavirin, a nucleoside polymerase or a protease inhibitor resulted in overall additive antiviral activity. Combinations containing GS-327073 proved highly effective in clearing hepatoma cells from HCV.
  
  
  CONCLUSIONS
  GS-327073 is a potent in vitro inhibitor of HCV replication either alone or in combination with other selective HCV inhibitors.
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedesstraat 10, 3000 Leuven, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Vliegen
authors.forename: Jan
authors.initials: J
authors.lastname: Paeshuyse
authors.forename: Tine
authors.initials: T
authors.lastname: De Burghgraeve
authors.forename: Laura S
authors.initials: LS
authors.lastname: Lehman
authors.forename: Matthew
authors.initials: M
authors.lastname: Paulson
authors.forename: I-Hung
authors.initials: IH
authors.lastname: Shih
authors.forename: Eric
authors.initials: E
authors.lastname: Mabery
authors.forename: Nina
authors.initials: N
authors.lastname: Boddeker
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Hans
authors.initials: H
authors.lastname: Reiser
authors.forename: David
authors.initials: D
authors.lastname: Oare
authors.forename: William A
authors.initials: WA
authors.lastname: Lee
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhong
authors.forename: Steven
authors.initials: S
authors.lastname: Bondy
authors.forename: Gerhard
authors.initials: G
authors.lastname: Pürstinger
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology; D011480:Protease Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D012367:RNA, Viral / Q000378:metabolism; D012254:Ribavirin / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C542798:5-((3-(4-chlorophenyl)-5-isoxazolyl)methyl)-2-(2,3-difluorophenyl)-5H-imidazo(4,5-c)pyridine; D000998:Antiviral Agents; D007093:Imidazoles; D011480:Protease Inhibitors; D011725:Pyridines; D012367:RNA, Viral; D012254:Ribavirin; D007372:Interferons