Abstract
A series of heterocyclic aza-analogs of BI 207524 (2), a potent HCV NS5B polymerase thumb pocket 1 inhibitor, was investigated with the goal to reduce the liability associated with the release of a genotoxic aniline metabolite in vivo. Analog 4, containing a 2-aminopyridine aniline isostere that is negative in the Ames test was identified, and was found to provide comparable GT1a/1b potency to 2. Although the cross-species PK profile, poor predicted human liver distribution of analog 4 and allometry principles projected high doses to achieve a strong antiviral response in patients, this work has provided a path forward toward the design of novel thumb pocket 1 NS5B polymerase inhibitors with improved safety profiles.
Keywords:
Ames; Antiviral; Genotoxicity; Hepatitis C virus; NS5B polymerase.
Copyright © 2014 Elsevier Ltd. All rights reserved.
MeSH terms
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Acrylates / chemistry
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Acrylates / metabolism*
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Acrylates / pharmacokinetics
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Acrylates / pharmacology*
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Aniline Compounds / metabolism*
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Animals
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Antiviral Agents / chemistry
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Antiviral Agents / metabolism*
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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 / metabolism
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Haplorhini
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Hepatitis C / drug therapy
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Hepatitis C / virology
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Humans
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Indoles / chemistry
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Indoles / metabolism*
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Indoles / pharmacokinetics
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Indoles / pharmacology*
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Rats
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
Substances
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(E)-3-(4-((1-((2-(5-chloro-pyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carbonyl)-amino)-cyclobutanecarbonyl)-amino)-2-ethoxy-phenyl)-acrylic acid
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Acrylates
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Aniline Compounds
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Antiviral Agents
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Enzyme Inhibitors
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Indoles
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Viral Nonstructural Proteins
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aniline