Abstract
A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile 21b, has an IC(50) of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Cell Proliferation / drug effects
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Fluorescence Polarization
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Genes, fos / genetics
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Macrophage Colony-Stimulating Factor / metabolism
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Macrophages / drug effects*
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Mice
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Mice, Inbred C57BL
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Molecular Structure
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology*
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Quinolones / chemical synthesis*
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Quinolones / pharmacokinetics
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Quinolones / pharmacology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
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Receptor, Macrophage Colony-Stimulating Factor / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Spleen / metabolism
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Structure-Activity Relationship
Substances
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4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile
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Protein Kinase Inhibitors
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Quinolones
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RNA, Messenger
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Macrophage Colony-Stimulating Factor
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Receptor, Macrophage Colony-Stimulating Factor