Abstract
A medicinal chemistry campaign that was conducted to address a potential genotoxic liability associated with an aniline-derived scaffold in a series of HCV NS5A inhibitors with dual GT-1a/-1b inhibitory activity is described. Anilides 3b and 3c were used as vehicles to explore structural modifications that retained antiviral potency while removing the potential for metabolism-based unmasking of the embedded aniline. This effort resulted in the discovery of a highly potent biarylimidazole chemotype that established a potency benchmark in replicon assays, particularly toward HCV GT-1a, a strain with significant clinical importance. Securing potent GT-1a activity in a chemotype class lacking overt structural liabilities was a critical milestone in the effort to realize the full clinical potential of targeting the HCV NS5A protein.
MeSH terms
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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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Crystallography, X-Ray
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Drug Discovery
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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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Genotype*
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Hepacivirus / genetics
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Hepacivirus / physiology
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Imidazoles / chemistry
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Imidazoles / pharmacokinetics
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Imidazoles / pharmacology*
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Magnetic Resonance Spectroscopy
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RNA-Dependent RNA Polymerase / antagonists & inhibitors*
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Replicon / drug effects*
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Spectrometry, Mass, Electrospray Ionization
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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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Imidazoles
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Viral Nonstructural Proteins
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NS-5 protein, hepatitis C virus
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RNA-Dependent RNA Polymerase