Selective inhibitors of tumor progression loci-2 (Tpl2) kinase with potent inhibition of TNF-α production in human whole blood

J Wu, N Green, R Hotchandani, Y Hu, J Condon…

Index: Wu, Junjun; Green, Neal; Hotchandani, Rajeev; Hu, Yonghan; Condon, Jeffrey; Huang, Adrian; Kaila, Neelu; Li, Huan-Qiu; Guler, Satenig; Li, Wei; Tam, Steve Y.; Wang, Qin; Pelker, Jeffrey; Marusic, Suzana; Hsu, Sang; Perry Hall; Telliez, Jean-Baptiste; Cui, Junqing; Lin, Lih-Ling Bioorganic and Medicinal Chemistry Letters, 2009 , vol. 19, # 13 p. 3485 - 3488

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Citation Number: 35

Abstract

Tpl2 (cot/MAP3K8) is an upstream kinase of MEK in the ERK pathway. It plays an important role in Tumor Necrosis Factor-α (TNF-α) 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-α production in LPS-stimulated human blood, a series of analogs with a ...