Development and preliminary optimization of indole-N-acetamide inhibitors of hepatitis C virus NS5B polymerase.
Allosteric inhibition of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase enzyme has recently emerged as a viable strategy toward blocking replication of viral RNA in cell-based systems. We report here a novel class of allosteric inhibitor of NS5B that shows potent affinity for the NS5B enzyme and effective inhibition of subgenomic HCV RNA replication in HUH-7 cells. Inhibitors from this class have promising characteristics for further development as anti-HCV agents.
Harper
Steven
S
IRBM (Merck Research Laboratories Rome), Via Pontina km 30,600, 00040 Pomezia, Rome, Italy. Steven_Harper@merck.com
Pacini
Barbara
B
Avolio
Salvatore
S
Di Filippo
Marcello
M
Migliaccio
Giovanni
G
Laufer
Ralph
R
De Francesco
Raffaele
R
Rowley
Michael
M
Narjes
Frank
F
D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000494:Allosteric Regulation; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012367:RNA, Viral / Q000096:biosynthesis / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
D000081:Acetamides; D007211:Indoles; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase