Abstract
We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin.
MeSH terms
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology
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Benzodiazepines / chemical synthesis*
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Benzodiazepines / chemistry
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Benzodiazepines / pharmacology
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Crystallography, X-Ray
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Hepacivirus / enzymology*
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Hepacivirus / genetics
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Models, Molecular
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Molecular Conformation
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RNA, Viral / genetics
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Replicon
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Serum Albumin
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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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Heterocyclic Compounds, 4 or More Rings
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Indoles
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RNA, Viral
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Serum Albumin
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Viral Nonstructural Proteins
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Benzodiazepines
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NS-5 protein, hepatitis C virus