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.

[摘要]：(Heterocyclic Compounds (More Than One Hetero Atom)) Section Three series of substituted 2-alkylsulfanyl-4-(4-fluorophenyl)imidazoles, 5-pyridinyl-, 1-methyl-5-pyridinyl-, and 5-(2-aminopyridin-4-yl)-imidazoles, were prepd. and tested for their ability to inhibit p38 MAP kinase and TNF-a release. These compds. were tested by applying a nonradioactive p38 MAP kinase assay and by measurement of TNF-a release in human whole blood. Potent inhibitors (IC50values 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 derivs. 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.

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