Abstract
The discovery of GS-9451 is reported. Modification of the P3 cap and P2 quinoline with a series of solubilizing groups led to the identification of potent HCV NS3 protease inhibitors with greatly improved pharmacokinetic properties in rats, dogs and monkeys.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology
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Biological Availability
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Caco-2 Cells
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Carboxylic Acids / chemical synthesis*
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Carboxylic Acids / pharmacokinetics
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Carboxylic Acids / pharmacology
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Crystallography, X-Ray
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Dogs
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Hepacivirus / chemistry
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Hepatitis C / drug therapy
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Hepatitis C / virology
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Humans
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Macaca fascicularis
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Models, Molecular
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Quinolines / chemical synthesis*
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Quinolines / pharmacokinetics
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Quinolines / pharmacology
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Rats
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / pharmacokinetics
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Serine Proteinase Inhibitors / pharmacology
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / chemistry
Substances
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Antiviral Agents
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Carboxylic Acids
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GS-9451
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NS3 protein, hepatitis C virus
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Quinolines
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Serine Proteinase Inhibitors
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Viral Nonstructural Proteins