Green, Neal; Hu, Yonghan; Janz, Kristin; Li, Huan-Qiu; Kaila, Neelu; Guler, Satenig; Thomason, Jennifer; Joseph-McCarthy, Diane; Tam, Steve Y.; Hotchandani, Rajeev; Wu, Junjun; Huang, Adrian; Wang, Qin; Leung, Louis; Pelker, Jefferey; Marusic, Suzana; Hsu, Sang; Telliez, Jean-Baptiste; Hall, J. Perry; Cuozzo, John W.; Lin, Lih-Ling published the artcile< Inhibitors of Tumor Progression Loci-2 (Tpl2) Kinase and Tumor Necrosis Factor α (TNF-α) Production: Selectivity and in Vivo Antiinflammatory Activity of Novel 8-Substituted-4-anilino-6-aminoquinoline-3-carbonitriles>, COA of Formula: C6H11NO2, the main research area is anilinoaminoquinoline carbonitrile derivative preparation structure Tpl2 kinase inhibitor antiinflammatory.
Tumor progression loci-2 (Tpl2) (Cot/MAP3K8) is a serine/threonine kinase in the MAP3K family directly upstream of MEK. Recent studies using Tpl2 knockout mice have indicated an important role for Tpl2 in the lipopolysaccharide (LPS) induced production of tumor necrosis factor α (TNF-α) 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 mol. modeling and crystallog. data of the EGFR kinase domain with and without an EGFR kinase-specific 4-anilinoquinazoline inhibitor (erlotinib, Tarceva), the authors hypothesized that the authors could diminish the inhibition of EGFR kinase by substitution at the C-8 position of the 4-anilino-6-aminoquinoline-3-carbonitrile leads. The 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles were prepared from the appropriate 2-substituted 4-nitroanilines. Modifications to the C-6 and C-8 positions led to the identification of compounds with increased inhibition of TNF-α release from LPS-stimulated rat and human blood, and these analogs were also highly selective for Tpl2 kinase over EGFR kinase. Further structure-activity based 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 vivo efficacy in inhibition of LPS-induced TNF-α production
Journal of Medicinal Chemistry published new progress about Anti-inflammatory agents. 6136-93-2 belongs to class nitriles-buliding-blocks, and the molecular formula is C6H11NO2, COA of Formula: C6H11NO2.
Referemce:
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts