Improved replicon cellular activity of non-nucleoside allosteric inhibitors of HCV NS5B polymerase: from benzimidazole to indole scaffolds.
Benzimidazole-based allosteric inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified to a variety of topologically related scaffolds. Replacement of the polar benzimidazole core by lipophilic indoles led to inhibitors with improved potency in the cell-based subgenomic HCV replicon system. Transposing the indole scaffold into a previously described series of benzimidazole-tryptophan amides generated the most potent inhibitors of HCV RNA replication in cell culture reported to date in this series (EC(50) approximately 50 nM).
Beaulieu
Pierre L
PL
Boehringer Ingelheim, Canada, Ltd., Research and Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5. pbeaulieu@lav.boehringer-ingelheim.com
Gillard
James
J
Bykowski
Darren
D
Brochu
Christian
C
Dansereau
Nathalie
N
Duceppe
Jean-Simon
JS
Haché
Bruno
B
Jakalian
Araz
A
Lagacé
Lisette
L
LaPlante
Steven
S
McKercher
Ginette
G
Moreau
Elaine
E
Perreault
Stéphane
S
Stammers
Timothy
T
Thauvette
Louise
L
Warrington
Jeff
J
Kukolj
George
G
D000494:Allosteric Regulation; D001562:Benzimidazoles / Q000494:pharmacology*; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D012093:Replicon / Q000187:drug effects*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
D001562:Benzimidazoles; D007211:Indoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase