Abstract
We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Amides / chemistry
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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 / pharmacology*
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Carbamates / chemistry
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Dose-Response Relationship, Drug
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Drug Resistance, Viral / genetics
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Guanidines / chemistry
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Hepacivirus / genetics
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Microbial Sensitivity Tests
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Molecular Structure
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Oxamic Acid / chemistry
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Rats
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / chemistry
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Serine Proteinase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Urea / chemistry
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
Substances
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Amides
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Antiviral Agents
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Carbamates
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Guanidines
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NS3 protein, hepatitis C virus
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Serine Proteinase Inhibitors
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Viral Nonstructural Proteins
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Urea
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dicyandiamido
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Oxamic Acid