Abstract
Tpl2 (cot/MAP3K8) is an upstream kinase of MEK in the ERK pathway. It plays an important role in Tumor Necrosis Factor-alpha (TNF-alpha) production and signaling. We have discovered that 8-halo-4-(3-chloro-4-fluoro-phenylamino)-6-[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitriles (4) are potent inhibitors of this enzyme. In order to improve the inhibition of TNF-alpha production in LPS-stimulated human blood, a series of analogs with a variety of substitutions around the triazole moiety were studied. We found that a cyclic amine group appended to the triazole ring could considerably enhance potency, aqueous solubility, and cell membrane permeability. Optimization of these cyclic amine groups led to the identification of 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile (34). In a LPS-stimulated rat inflammation model, compound 34 showed good efficacy in inhibiting TNF-alpha production.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry*
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Anti-Inflammatory Agents / pharmacokinetics
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Female
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Humans
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Lipopolysaccharides / pharmacology
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MAP Kinase Kinase Kinases / antagonists & inhibitors*
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MAP Kinase Kinase Kinases / metabolism
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Monocytes / drug effects
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Monocytes / immunology
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Nitriles / chemical synthesis
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Nitriles / chemistry*
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Nitriles / pharmacokinetics
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / metabolism
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Quinolines / chemical synthesis
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Quinolines / chemistry*
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Quinolines / pharmacokinetics
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Rats
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Rats, Sprague-Dawley
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / blood*
Substances
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8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile
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Anti-Inflammatory Agents
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Lipopolysaccharides
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Nitriles
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Quinolines
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Tumor Necrosis Factor-alpha
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MAP Kinase Kinase Kinases
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MAP3K8 protein, human