Abstract
The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.
MeSH terms
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / pharmacology
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Caco-2 Cells
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Chemistry, Pharmaceutical / methods*
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Crystallography, X-Ray / methods
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Cyclic S-Oxides / chemical synthesis*
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Cyclic S-Oxides / pharmacology
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DNA-Directed RNA Polymerases / chemistry
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Drug Design
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Genotype
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Humans
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Inhibitory Concentration 50
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Microsomes / metabolism
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Models, Chemical
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Molecular Conformation
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Pyridazines / chemical synthesis*
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Pyridazines / chemistry*
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Pyridazines / pharmacology
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Structure-Activity Relationship
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Thiadiazines / chemical synthesis*
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Thiadiazines / pharmacology
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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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Cyclic S-Oxides
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Pyridazines
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Thiadiazines
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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