Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery of benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency.
Optimization of benzimidazole 5-carboxamide derivatives previously identified as specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV) has led to the discovery of potent analogues that inhibit the enzyme at low-nanomolar concentrations. Greater than 800-fold improvement in potency from the original lead structure was achieved through the combined effects of conformational rigidification, molecular size extension and the identification of previously unexploited interactions. Furthermore, these inhibitors retain specificity for HCV polymerase relative to other viral and mammalian RNA polymerases.
Beaulieu
Pierre L
PL
Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5. pbeaulieu@lav.boehringer-ingelheim.com
Bös
Michael
M
Bousquet
Yves
Y
DeRoy
Patrick
P
Fazal
Gulrez
G
Gauthier
Jean
J
Gillard
James
J
Goulet
Sylvie
S
McKercher
Ginette
G
Poupart
Marc-André
MA
Valois
Serge
S
Kukolj
George
G
D000577:Amides / Q000737:chemistry*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D015394:Molecular Structure; D017955:Poliovirus / Q000201:enzymology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D000998:Antiviral Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; D012321:DNA-Directed RNA Polymerases