Abstract
Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.
MeSH terms
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Animals
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Hepacivirus / enzymology*
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Macrocyclic Compounds / chemical synthesis
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Macrocyclic Compounds / chemistry*
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Macrocyclic Compounds / pharmacokinetics
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Macrocyclic Compounds / pharmacology
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Models, Molecular
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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 / pharmacokinetics
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Serine Proteinase Inhibitors / pharmacology
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / chemistry
Substances
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Macrocyclic Compounds
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NS3 protein, hepatitis C virus
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Serine Proteinase Inhibitors
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Viral Nonstructural Proteins