Abstract
By reducing the basicity of the core heterocycle in a series of HCV NS5B inhibitors, the hERG liability was reduced. The SAR was then systematically explored in order to increase solubility and enable dose escalation while retaining potency. During this exploration, a facile decarboxylation was noted and was exploited as a novel prodrug mechanism. The synthesis and characterization of these prodrugs and their utilization in chronic toxicity studies are presented.
MeSH terms
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Animals
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology*
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Dogs
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Magnetic Resonance Spectroscopy
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Mass Spectrometry
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Pyridazines / chemistry
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Pyridazines / pharmacokinetics
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Pyridazines / pharmacology*
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Rats
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
Substances
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Antiviral Agents
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Enzyme Inhibitors
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Pyridazines
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Viral Nonstructural Proteins
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pyridazine
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NS-5 protein, hepatitis C virus