Abstract
A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.
MeSH terms
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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 / pharmacokinetics
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Computer Simulation
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Crystallography, X-Ray
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DNA-Directed RNA Polymerases / antagonists & inhibitors*
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DNA-Directed RNA Polymerases / metabolism
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Dogs
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Hepacivirus / drug effects*
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Humans
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Quinolines / chemical synthesis
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Quinolines / chemistry*
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Quinolines / pharmacokinetics
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Quinolones / chemical synthesis
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Quinolones / chemistry*
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Quinolones / pharmacology
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Rats
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Structure-Activity Relationship
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Thiazines / chemical synthesis
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Thiazines / chemistry*
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Thiazines / pharmacology
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
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Virus Replication / drug effects
Substances
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Antiviral Agents
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Enzyme Inhibitors
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Quinolines
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Quinolones
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Thiazines
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Viral Nonstructural Proteins
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NS-5 protein, hepatitis C virus
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DNA-Directed RNA Polymerases