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
Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA.
Bioorg Med Chem Lett. 2006 Dec 1;16(23):6067-72. doi: 10.1016/j.bmcl.2006.08.102. Epub 2006 Sep 14.
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.
本文描述了一系列喹啉-3-腈作为Tpl2激酶抑制剂的合成及构效关系研究。在酶促试验中，确定了对一组选定激酶具有选择性且在LPS处理的人单核细胞的基于细胞的磷酸化试验中具有特异性的Tpl2激酶强效抑制剂。在人全血试验中具有中等活性的选定抑制剂，经腹腔注射给予小鼠后，可有效抑制LPS/D-半乳糖诱导的TNFα释放。
