Abstract
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology
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Biological Availability
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Cell Line, Tumor
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Crystallography, X-Ray
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Dogs
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Hepacivirus / physiology
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Humans
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Indoles / chemical synthesis*
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Macaca mulatta
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Mice
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Mice, SCID
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Mice, Transgenic
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Models, Molecular
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Molecular Structure
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Oxazocines / chemical synthesis*
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Oxazocines / pharmacokinetics
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Oxazocines / pharmacology
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RNA-Dependent RNA Polymerase / antagonists & inhibitors*
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Rats
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Rats, Sprague-Dawley
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Stereoisomerism
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viremia / drug therapy
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Viremia / virology
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Virus Replication / drug effects
Substances
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14-cyclohexyl-7-((2-(dimethylamino)ethyl)(methyl)amino)-7,8-dihydro-6H-indolo(1,2-e)(1,5)benzoxazocine-11-carboxylic acid
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Antiviral Agents
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Indoles
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Oxazocines
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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