Targeting the ribose and phosphate binding site of p38 mitogen-activated protein (MAP) kinase: synthesis and biological testing of 2-alkylsulfanyl-, 4(5)-aryl-, 5(4)-heteroaryl-substituted imidazoles.
Three series of substituted 2-alkylsulfanyl-4-(4-fluorophenyl)imidazoles, 5-pyridinyl-, 1-methyl-5-pyridinyl-, and 5-(2-aminopyridin-4-yl)-imidazoles, were prepared and tested for their ability to inhibit p38 MAP kinase and TNF-alpha release. These compounds were prepared by using different synthetic routes. They were tested by applying a nonradioactive p38 MAP kinase assay and by measurement of TNF-alpha release in human whole blood. Potent inhibitors (IC50 values in the low nanomolar range, as low as 2 nM in the enzyme assay and 37 nM in the human whole blood test) were identified by variation of substituents at the imidazole- C2-thio position as well as at the 2-aminopyridinyl functionality. In contrast to other known kinase inhibitors, these novel imidazole derivatives with the substituents at the imidazole-C2-thio position may interact with the ribose as well as with the phosphate binding site of the p38 MAP kinase.
Pierre Koch
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Christiane Bäuerlein
Hartmut Jank
Stefan Laufer