Abstract
From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.
MeSH terms
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Administration, Oral
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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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Biological Availability
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Carbamates / chemical synthesis*
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Carbamates / chemistry
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Carbamates / pharmacology
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Hepacivirus / enzymology*
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Heterocyclic Compounds / chemical synthesis*
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / pharmacology
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Injections, Intravenous
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Proline / chemistry
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology
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Rats
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
Substances
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Antiviral Agents
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Carbamates
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Heterocyclic Compounds
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NS3 protein, hepatitis C virus
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Protease Inhibitors
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Viral Nonstructural Proteins
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Proline