Abstract
Screening of a focused library of TGF beta kinase inhibitors in the cellular HCV replicon model with luciferase read out yielded a number of low micromolar HCV inhibitors. Medicinal chemistry driven optimization resulted in the discovery of 4-[2-(5-bromo-2-fluoro-phenyl)pteridin-4-ylamino]-N-[3-(2- oxopyrrolidin-1-yl)propyl]nicotinamide 36 with a replicon EC(50) of 64nM, associated with a selective kinase inhibitory profile for human JNK kinases 2 and 3 as well as VEGFR-1, 2, and 3 kinases. Moreover, 36 showed an advantageous PK profile in mice. Experiments performed using different replicon constructs suggest that this series of kinase inhibitors might mediate their effect through the HCV non-structural protein 5A (NS5A).
MeSH terms
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / pharmacology*
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Area Under Curve
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Cell Line
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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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Evaluation Studies as Topic
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Hepacivirus / metabolism*
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Humans
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Inhibitory Concentration 50
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MAP Kinase Kinase 4 / antagonists & inhibitors*
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Male
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Mice
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Models, Chemical
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Molecular Conformation
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Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors*
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Viral Nonstructural Proteins / chemistry
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Viral Nonstructural Proteins / pharmacology*
Substances
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Antiviral Agents
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Enzyme Inhibitors
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Viral Nonstructural Proteins
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Vascular Endothelial Growth Factor Receptor-1
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MAP Kinase Kinase 4
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NS-5 protein, hepatitis C virus