N-Acetamideindolecarboxylic acid allosteric 'finger-loop' inhibitors of the hepatitis C virus NS5B polymerase: discovery and initial optimization studies.
SAR studies at the N(1)-position of allosteric indole-based HCV NS5B inhibitors has led to the discovery of acetamide derivatives with good cellular potency in subgenomic replicons (EC(50) <200 nM). This class of inhibitors displayed improved physicochemical properties and favorable ADME-PK profiles over previously described analogs in this class.
Beaulieu
Pierre L
PL
Department of Chemistry, Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5. pierre.beaulieu@boehringer-ingelheim.com
Jolicoeur
Eric
E
Gillard
James
J
Brochu
Christian
C
Coulombe
René
R
Dansereau
Nathalie
N
Duan
Jianmin
J
Garneau
Michel
M
Jakalian
Araz
A
Kühn
Peter
P
Lagacé
Lisette
L
LaPlante
Steven
S
McKercher
Ginette
G
Perrault
Stéphane
S
Poirier
Martin
M
Poupart
Marc-André
MA
Stammers
Timothy
T
Thauvette
Louise
L
Thavonekham
Bounkham
B
Kukolj
George
G
D000081:Acetamides / Q000737:chemistry* / Q000494:pharmacology; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018938:Caco-2 Cells; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000081:Acetamides; D000998:Antiviral Agents; D002264:Carboxylic Acids; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; D012321:DNA-Directed RNA Polymerases