Inhibition of Tpl2 kinase and TNFalpha production with quinoline-3-carbonitriles for the treatment of rheumatoid arthritis

The synthesis and structure-activity studies of a series of quinoline-3-carbonitriles as inhibitors of Tpl2 kinase are described. Potent inhibitors of Tpl2 kinase with selectivity against a panel of selected kinases in enzymatic assays and specificity in cell-based phosphorylation assays in LPS-trea...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2006-12, Vol.16 (23), p.6067
Hauptverfasser:	Hu, Yonghan, Green, Neal, Gavrin, Lori K, Janz, Kristin, Kaila, Neelu, Li, Huan-Qiu, Thomason, Jennifer R, Cuozzo, John W, Hall, J Perry, Hsu, Sang, Nickerson-Nutter, Cheryl, Telliez, Jean-Baptiste, Lin, Lih-Ling, Tam, Steve
Format:	Artikel
Sprache:	eng
Schlagworte:	Arthritis, Rheumatoid - drug therapy Arthritis, Rheumatoid - metabolism Cross-Linking Reagents - chemistry Humans Imidazoles - chemistry MAP Kinase Kinase Kinases - antagonists & inhibitors MAP Kinase Kinase Kinases - metabolism Molecular Structure Monocytes - drug effects Monocytes - metabolism Nitriles - chemical synthesis Nitriles - chemistry Nitriles - pharmacology Quinolines - chemistry Structure-Activity Relationship Tumor Necrosis Factor-alpha - biosynthesis
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Zusammenfassung:	The synthesis and structure-activity studies of a series of quinoline-3-carbonitriles as inhibitors of Tpl2 kinase are described. Potent inhibitors of Tpl2 kinase with selectivity against a panel of selected kinases in enzymatic assays and specificity in cell-based phosphorylation assays in LPS-treated human monocytes were identified. Selected inhibitors with moderate activity in human whole blood assay effectively inhibited LPS/D-Gal induced TNFalpha release when administered intraperitoneally in mice.
ISSN:	0960-894X