Abstract
Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
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 / pharmacology
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Benzothiadiazines / chemical synthesis*
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Benzothiadiazines / chemistry
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Benzothiadiazines / pharmacology
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Biological Availability
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Blood Proteins / metabolism
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Cell Line
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Crystallography, X-Ray
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Dogs
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Genotype
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Half-Life
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Hepacivirus / enzymology*
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Hepacivirus / genetics
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Macaca fascicularis
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Models, Molecular
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Molecular Structure
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Mutation
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Protein Binding
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Quinolones / chemical synthesis*
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Quinolones / chemistry
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Quinolones / pharmacology
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RNA-Dependent RNA Polymerase / antagonists & inhibitors*
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RNA-Dependent RNA Polymerase / chemistry
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Thiadiazines / chemical synthesis*
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Thiadiazines / chemistry
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Thiadiazines / pharmacology
Substances
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1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone
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Antiviral Agents
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Benzothiadiazines
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Blood Proteins
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Quinolones
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Thiadiazines
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RNA-Dependent RNA Polymerase