Abstract
Novel conformationaly constrained 1,6- and 2,6-macrocyclic HCV NS5b polymerase inhibitors, in which either the nitrogen or the phenyl ring in the C2 position of the central indole core is tethered to an acylsulfamide acid bioisostere, have been designed and tested for their anti-HCV potency. This transformational route toward non-zwitterionic finger loop-directed inhibitors led to the discovery of derivatives with improved cell potency and pharmacokinetic profile.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Allosteric Regulation
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Animals
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Antiviral Agents / chemical synthesis
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Antiviral Agents / chemistry*
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Antiviral Agents / pharmacokinetics
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Cell Line, Tumor
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Hepacivirus / enzymology*
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Humans
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Indoles / chemical synthesis
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Indoles / chemistry*
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Indoles / pharmacokinetics
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Microsomes, Liver / metabolism
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
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Virus Replication / drug effects
Substances
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Antiviral Agents
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Enzyme Inhibitors
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Indoles
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Viral Nonstructural Proteins
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NS-5 protein, hepatitis C virus