Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 2: tertiary amides.
Further SAR studies on the thiophene-2-carboxylic acids are reported. These studies led to the identification of a series of tertiary amides that show inhibition of both HCV NS5B polymerase in vitro and HCV subgenomic RNA replication in Huh-7 cells. Structural insights about the bioactive conformation of this class of molecules were deduced from a combination of modeling and transferred NOE (trNOE) studies.
Chan
Laval
L
Shire BioChem Inc, 275 Armand-Frappier, Laval, Quebec, Canada H7V 4A7. lchan@ca.shire.com
Pereira
Oswy
O
Reddy
T Jagadeeswar
TJ
Das
Sanjoy K
SK
Poisson
Carl
C
Courchesne
Marc
M
Proulx
Mélanie
M
Siddiqui
Arshad
A
Yannopoulos
Constantin G
CG
Nguyen-Ba
Nghe
N
Roy
Caroline
C
Nasturica
Daniel
D
Moinet
Christophe
C
Bethell
Richard
R
Hamel
Martine
M
L'Heureux
Lucille
L
David
Maud
M
Nicolas
Olivier
O
Courtemanche-Asselin
Philippe
P
Brunette
Stéphanie
S
Bilimoria
Darius
D
Bédard
Jean
J
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000201:enzymology / Q000821:virology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016679:Genome, Viral; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D008113:Liver Neoplasms / Q000737:chemistry / Q000201:enzymology / Q000821:virology; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D012367:RNA, Viral / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D012093:Replicon / Q000187:drug effects; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
D000577:Amides; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D012367:RNA, Viral; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C550746:2-thiophene carboxylic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase