Selective inhibitors of tumor progression loci-2 (Tpl2) kinase with potent inhibition of TNF-alpha production in human whole blood.
Bioorg Med Chem Lett, 2009/7/01;19(13):3485-8.
Wu J[1], Green N, Hotchandani R, Hu Y, Condon J, Huang A, Kaila N, Li HQ, Guler S, Li W, Tam SY, Wang Q, Pelker J, Marusic S, Hsu S, Perry Hall J, Telliez JB, Cui J, Lin LL
Affiliations
PMID: 19464884DOI: 10.1016/j.bmcl.2009.05.009
Impact factor: 2.94
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
Animals; Anti-Inflammatory Agents; Female; Humans; Lipopolysaccharides; MAP Kinase Kinase Kinases; Monocytes; Nitriles; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Quinolines; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha
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