Inhibition of Tp12 kinase and TNFα 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 Tp12 kinase are described. Potent inhibitors of Tp12 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 TNF alpha release when administered intraperitoneally in mice. (c) 2006 Elsevier Ltd. All rights reserved.