Abstract
HCV-NS3 protease is essential for viral replication and NS3 protease inhibitors have shown proof of concept in clinical trials. Novel P2-P4 macrocycle inhibitors of NS3/4A comprising a P1 C-terminal carboxylic acid have recently been disclosed. A series of analogs, in which the carboxylic residue is replaced by phosphorous acid functionalities were synthesized and found to be inhibitors of the NS3 protease. Among them the methylphosphinate analogue showed nanomolar level of enzyme inhibition and sub-micromolar potency in the replication assay.
MeSH terms
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / pharmacology
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Chemistry, Pharmaceutical / methods*
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology
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Hepatitis C / drug therapy
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Humans
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Inhibitory Concentration 50
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Models, Chemical
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Molecular Structure
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Phosphates / chemistry
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Protease 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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Enzyme Inhibitors
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NS3 protein, hepatitis C virus
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Phosphates
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Protease Inhibitors
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Viral Nonstructural Proteins