Abstract
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.
MeSH terms
-
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*
Substances
-
Cross-Linking Reagents
-
Imidazoles
-
Nitriles
-
Quinolines
-
Tumor Necrosis Factor-alpha
-
imidazole
-
quinoline
-
MAP Kinase Kinase Kinases