Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery and preliminary SAR of benzimidazole derivatives.
Benzimidazole 5-carboxamide derivatives from a combinatorial screening library were discovered as specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV). Initial hit-to-lead activities taking advantage of high-throughput parallel synthetic techniques, identified a 1,2-disubstituted benzimidazole 5-carboxylic acid scaffold as the minimum core for biological activity. Potent analogues in this series inhibit the polymerase at low micromolar concentrations and provide an attractive "drug-like" lead structure for further optimization and the development of potential HCV therapeutics.
Beaulieu
Pierre L
PL
Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, H7S 2G5, Laval (Québec), Canada. pbeaulieu@lav.boehringer-ingelheim.com
Bös
Michael
M
Bousquet
Yves
Y
Fazal
Gulrez
G
Gauthier
Jean
J
Gillard
James
J
Goulet
Sylvie
S
LaPlante
Steven
S
Poupart
Marc-André
MA
Lefebvre
Sylvain
S
McKercher
Ginette
G
Pellerin
Charles
C
Austel
Volkhard
V
Kukolj
George
G
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000998:Antiviral Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase