Abstract
Described herein is the development of a potent non-nucleoside, small molecule inhibitor of genotype 1 HCV NS5B Polymerase. A 23 μM inhibitor that was active against HCV polymerase was further elaborated into a potent single-digit nanomolar inhibitor of HCV NS5B polymerase by additional manipulation of the R and R1 substituents. Subsequent modifications to improve physical properties were made in an attempt to achieve an acceptable pharmacokinetic profile.
Copyright © 2013. Published by Elsevier Ltd.
MeSH terms
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacokinetics
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Half-Life
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Hepacivirus / enzymology*
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Hepacivirus / physiology
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Rats
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Structure-Activity Relationship
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Uracil / analogs & derivatives*
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Uracil / chemical synthesis
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Uracil / pharmacokinetics
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
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Virus Replication / drug effects
Substances
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Antiviral Agents
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Viral Nonstructural Proteins
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Uracil
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NS-5 protein, hepatitis C virus