Abstract
A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production. Unlike the IL-2 inhibitors, cyclosporine and FK506, the BTPs do not directly inhibit the dephosphorylation of NFAT by calcineurin.
MeSH terms
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Animals
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Asthma / drug therapy
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Cell Division
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Chemokine CCL11
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Chemokines, CC*
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Combinatorial Chemistry Techniques
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Cyclosporine / pharmacology
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Cytokines / antagonists & inhibitors
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Cytokines / biosynthesis
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DNA-Binding Proteins / metabolism*
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Genes, Reporter
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Haplorhini
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Humans
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Immunosuppressive Agents / chemical synthesis
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Immunosuppressive Agents / chemistry
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Immunosuppressive Agents / pharmacology
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In Vitro Techniques
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / biosynthesis
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Interleukin-4 / antagonists & inhibitors
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Interleukin-4 / biosynthesis
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Interleukin-5 / antagonists & inhibitors
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Interleukin-5 / biosynthesis
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Interleukin-8 / antagonists & inhibitors
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Interleukin-8 / biosynthesis
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Jurkat Cells
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Leukocytes, Mononuclear / cytology
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Leukocytes, Mononuclear / drug effects
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Luciferases / genetics
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NFATC Transcription Factors
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Nuclear Proteins*
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Protein Synthesis Inhibitors / chemical synthesis*
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Protein Synthesis Inhibitors / chemistry
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Protein Synthesis Inhibitors / pharmacology
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Rats
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Transcription Factors / metabolism*
Substances
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CCL11 protein, human
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Ccl11 protein, rat
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Chemokine CCL11
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Chemokines, CC
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Cytokines
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DNA-Binding Proteins
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Immunosuppressive Agents
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Interleukin-2
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Interleukin-5
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Interleukin-8
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NFATC Transcription Factors
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Nuclear Proteins
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Protein Synthesis Inhibitors
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Pyrazoles
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Transcription Factors
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Interleukin-4
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Cyclosporine
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Luciferases