Abstract
A series of N-substituted 3-aminoglutarimides have been synthesized and tested for inhibitory activity against a range of chemokines in vitro and for suppression of lipopolysaccharide-induced inflammation in vivo. The results show that they represent the first class of small molecules with broad-spectrum chemokine inhibitory effects. Among the compounds studied, 10 (NR58,4) was the most potent, being active at doses between 5 and 15 nM in vitro and at 0.3 mg kg(-1) in vivo.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Cell Line
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Chemokine CCL2 / chemistry*
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Chemokine CCL2 / pharmacology
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Chemokines / antagonists & inhibitors*
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Chemotaxis, Leukocyte / drug effects
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Humans
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Lipopolysaccharides / pharmacology
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Male
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Mice
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Molecular Mimicry
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Oligopeptides / chemistry*
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Oligopeptides / pharmacology
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Peptide Fragments / chemistry
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Peptide Fragments / pharmacology
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Piperidones / chemical synthesis*
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Piperidones / chemistry
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Piperidones / pharmacology
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Receptors, Chemokine / antagonists & inhibitors*
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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3-(undec-10-enoylamino)glutarimide
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Anti-Inflammatory Agents, Non-Steroidal
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Chemokine CCL2
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Chemokines
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Lipopolysaccharides
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Oligopeptides
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Peptide Fragments
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Piperidones
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Receptors, Chemokine
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Tumor Necrosis Factor-alpha