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 Jul 1;19(13):3485-8. doi: 10.1016/j.bmcl.2009.05.009.
Junjun Wu  1 ,  Neal Green ,  Rajeev Hotchandani ,  Yonghan Hu ,  Jeffrey Condon ,  Adrian Huang ,  Neelu Kaila ,  Huan-Qiu Li ,  Satenig Guler ,  Wei Li ,  Steve Y Tam ,  Qin Wang ,  Jeffrey Pelker ,  Suzana Marusic ,  Sang Hsu ,  J Perry Hall ,  Jean-Baptiste Telliez ,  Junqing Cui ,  Lih-Ling Lin
Affiliations
  • 1. Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. [email protected]
PMID: 19464884 DOI: 10.1016/j.bmcl.2009.05.009
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.

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