Abstract
The isoquinolinamide series of HCV NS5A inhibitors exemplified by compounds 2b and 2c provided the first dual genotype-1a/1b (GT-1a/1b) inhibitor class that demonstrated a significant improvement in potency toward GT-1a replicons compared to that of the initial program lead, stilbene 2a. Structure-activity relationship (SAR) studies that uncovered an alternate phenylglycine-based cap series that exhibit further improvements in virology profile, along with some insights into the pharmacophoric elements associated with the GT-1a potency, are described.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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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Crystallography, X-Ray
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Drug Evaluation, Preclinical
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Genotype
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Glycine / analogs & derivatives*
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Glycine / chemical synthesis
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Glycine / chemistry
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Glycine / pharmacokinetics
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Half-Life
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Hepacivirus / enzymology*
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Hepacivirus / genetics
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Hepacivirus / physiology
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Microsomes, Liver / metabolism
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Molecular Conformation
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Rats
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Structure-Activity Relationship
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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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glycine amide
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NS-5 protein, hepatitis C virus
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Glycine