Abstract
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
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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Binding Sites
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Crystallography, X-Ray
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Hepacivirus / drug effects*
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Pyrrolidinones / chemical synthesis
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Pyrrolidinones / chemistry*
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Pyrrolidinones / pharmacokinetics
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Rats
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Structure-Activity Relationship
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Thiazines / chemistry*
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
Substances
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Antiviral Agents
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Pyrrolidinones
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Thiazines
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Viral Nonstructural Proteins
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tetramic acid
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NS-5 protein, hepatitis C virus