Inhibitors of Tumor Progression Loci-2 (Tpl2) Kinase and Tumor Necrosis Factor (TNF-) Production: Selectivity and in Vivo Antiinflammatory Activity of Novel 8-Substituted-4-anilino-6-aminoquinoline-3

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• 作者：Neal Green ; Yonghan Hu ; Kristin Janz ; Huan-Qiu Li ; Neelu Kaila ; Satenig Guler ; Jennifer Thomason ; Diane Joseph-McCarthy ; Steve Y. Tam ; Rajeev Hotchandani ; Junjun Wu ; Adrian Huang ; Qin Wang ; Louis Leun
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：September 20, 2007
• 年：2007
• 卷：50
• 期：19
• 页码：4728 - 4745
• 全文大小：390K
• 年卷期：v.50,no.19(September 20, 2007)
• ISSN：1520-4804

文摘

Tumor progression loci-2 (Tpl2) (Cot/MAP3K8) is a serine/threonine kinase in the MAP3K family directlyupstream of MEK. Recent studies using Tpl2 knockout mice have indicated an important role for Tpl2 inthe lipopolysaccharide (LPS) induced production of tumor necrosis factor (TNF-) and other proinflammatory cytokines involved in diseases such as rheumatoid arthritis. Initial 4-anilino-6-aminoquinoline-3-carbonitrile leads showed poor selectivity for Tpl2 over epidermal growth factor receptor (EGFR) kinase.Using molecular modeling and crystallographic data of the EGFR kinase domain with and without an EGFRkinase-specific 4-anilinoquinazoline inhibitor (erlotinib, Tarceva), we hypothesized that we could diminishthe inhibition of EGFR kinase by substitution at the C-8 position of our 4-anilino-6-aminoquinoline-3-carbonitrile leads. The 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles were prepared from theappropriate 2-substituted 4-nitroanilines. Modifications to the C-6 and C-8 positions led to the identificationof compounds with increased inhibition of TNF- release from LPS-stimulated rat and human blood, andthese analogues were also highly selective for Tpl2 kinase over EGFR kinase. Further structure-activitybased modifications led to the identification of 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-[(1-methyl-1H-imidazol-4-yl)methylamino]quinoline-3-carbonitrile, which demonstrated in vitro as well as in vivoefficacy in inhibition of LPS-induced TNF- production.