Synthesis and evaluation of novel potent HCV NS5A inhibitors

Judicious modifications to the structure of the previously reported HCV NS5A inhibitor 1, resulted in more potent anti-HCV compounds with similar and in some cases improved toxicity profiles. The synthesis of 19 new NS5A inhibitors is reported along with their ability to block HCV replication in an...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-07, Vol.22 (14), p.4864-4868
Main Authors: Zhang, Hongwang, Zhou, Longhu, Amblard, Franck, Shi, Junxing, Bobeck, Drew R., Tao, Sijia, McBrayer, Tamara R., Tharnish, Phillip M., Whitaker, Tony, Coats, Steven J., Schinazi, Raymond F.
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral
Antiviral agents
Antiviral Agents - chemical synthesis
Antiviral Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Cell Survival - drug effects
chemical compounds
chemistry
enzymes
HCV
Hepacivirus - drug effects
Humans
liver microsomes
Medical sciences
Microsomes, Liver - drug effects
Molecular Structure
NS5A
Pharmacology. Drug treatments
replicon
Structure-Activity Relationship
toxicity
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Summary:Judicious modifications to the structure of the previously reported HCV NS5A inhibitor 1, resulted in more potent anti-HCV compounds with similar and in some cases improved toxicity profiles. The synthesis of 19 new NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. For the most potent compounds chemical stability, stability in liver microsomes and inhibition of relevant CYP450 enzymes is also presented.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.05.039