Selective inhibitors of tumor progression loci-2 (Tpl2) kinase with potent inhibition of TNF-α production in human whole blood
| Autor: | Rajeev Hotchandani, Neal Jeffrey Green, Junqing Cui, Suzana Marusic, Wei Li, Yonghan Hu, Neelu Kaila, J. Perry Hall, Tam Steve Yik-Kai, Lih-Ling Lin, Jeffrey W. Pelker, Sang Hsu, Huan-Qiu Li, Adrian Huang, Jeffrey Scott Condon, Qin Wang, Jean-Baptiste Telliez, Junjun Wu, Satenig Guler |
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| Rok vydání: | 2009 |
| Předmět: |
Lipopolysaccharides
MAPK/ERK pathway Clinical Biochemistry Anti-Inflammatory Agents Triazole Pharmaceutical Science Biochemistry MAP3K8 Monocytes Rats Sprague-Dawley chemistry.chemical_compound Proto-Oncogene Proteins Nitriles Drug Discovery Animals Humans Protein Kinase Inhibitors Molecular Biology chemistry.chemical_classification MAP kinase kinase kinase Tumor Necrosis Factor-alpha Kinase Organic Chemistry Aromatic amine Biological activity MAP Kinase Kinase Kinases Rats chemistry Quinolines Molecular Medicine Female Signal transduction |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 19:3485-3488 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2009.05.009 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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