Benzimidazole Thumb Pocket I finger-loop inhibitors of HCV NS5B polymerase: improved drug-like properties through C-2 SAR in three sub-series.
SAR at the C-2 position of benzimidazole-based Thumb Pocket I inhibitors of HCV NS5B polymerase revealed parallel activity for distinct sub-series that harbor 5-hydroxytryptophan amides, neutral thiazole isosteres or recently disclosed cinnamic acid diamides. The consistent SAR among the three sub-series suggest a common binding mode to the Thumb Pocket I allosteric site. New inhibitors with sub-micromolar cell-based replicon potency and improved 'drug-like' features are disclosed along with preliminary characterization of their ADME-PK profile.
Beaulieu
Pierre L
PL
Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, Laval, Québec, Canada. pierre.beaulieu@boehringer-ingelheim.com
Dansereau
Nathalie
N
Duan
Jianmin
J
Garneau
Michel
M
Gillard
James
J
McKercher
Ginette
G
LaPlante
Steven
S
Lagacée
Lisette
L
Thauvette
Louise
L
Kukolj
George
G
D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase