Substituted imidazopyridines as potent inhibitors of HCV replication.
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.
Vliegen
Inge
I
Rega Institute for Medical Research, KU Leuven, Minderbroedesstraat 10, 3000 Leuven, Belgium.
Paeshuyse
Jan
J
De Burghgraeve
Tine
T
Lehman
Laura S
LS
Paulson
Matthew
M
Shih
I-Hung
IH
Mabery
Eric
E
Boddeker
Nina
N
De Clercq
Erik
E
Reiser
Hans
H
Oare
David
D
Lee
William A
WA
Zhong
Weidong
W
Bondy
Steven
S
Pürstinger
Gerhard
G
Neyts
Johan
J
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*
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