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 conformati...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2004-02, Vol.14 (3), p.797-800
Main Authors: Chan, Laval, Pereira, Oswy, Reddy, T.Jagadeeswar, Das, Sanjoy K., Poisson, Carl, Courchesne, Marc, Proulx, Mélanie, Siddiqui, Arshad, Yannopoulos, Constantin G., Nguyen-Ba, Nghe, Roy, Caroline, Nasturica, Daniel, Moinet, Christophe, Bethell, Richard, Hamel, Martine, L'Heureux, Lucille, David, Maud, Nicolas, Olivier, Courtemanche-Asselin, Philippe, Brunette, Stéphanie, Bilimoria, Darius, Bédard, Jean
Format: Article
Language:English
Subjects:
Amides - chemistry
Amides - pharmacology
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
Carboxylic Acids
Carcinoma, Hepatocellular - chemistry
Carcinoma, Hepatocellular - enzymology
Carcinoma, Hepatocellular - virology
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Genome, Viral
Hepacivirus - enzymology
Humans
Liver Neoplasms - chemistry
Liver Neoplasms - enzymology
Liver Neoplasms - virology
Magnetic Resonance Spectroscopy
Medical sciences
Molecular Conformation
Molecular Structure
Pharmacology. Drug treatments
Replicon - drug effects
RNA, Viral - metabolism
RNA-Dependent RNA Polymerase - antagonists & inhibitors
Structure-Activity Relationship
Thiophenes - chemistry
Thiophenes - pharmacology
Viral Nonstructural Proteins - antagonists & inhibitors
Virus Replication - drug effects
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Summary: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. Graphic
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2003.10.068