1. Selective inhibitors of tumor progression loci-2 (Tpl2) kinase with potent inhibition of TNF-α production in human whole blood
- Author
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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, and Satenig Guler
- Subjects
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 - 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.
- Published
- 2009