Synthesis and structure-activity relationships of 4-fluorophenyl-imidazole p38α MAPK, CK1δ and JAK2 kinase inhibitors.

The synthesis and structure-activity relationships of novel 4-(4'-fluorophenyl)imidazoles as selective p38α MAPK, CK1δ and JAK2 inhibitors with improved water solubility are described. Microwave-assisted multicomponent reactions afforded 4-fluorophenyl-2,5-disubstituted imidazoles. Carboxylate and phosphonate groups were introduced via 'click' reactions. The kinase selectivity was influenced by the heteroaryl group at imidazole C-5 and the position of a carboxylic acid or tetrazole at imidazole C-2. For example, pyrimidines 15 and 34 inhibited p38α MAPK with IC50=250 nM and 96 nM, respectively. Pyridine 3 gave CK1δ inhibition with IC50=89 nM and pyridin-2-one 31 gave JAK2 inhibition with IC50=62 nM.

Syntheses and structure-activity relationships for some triazolyl p38α MAPK inhibitors.

The design, synthesis and biological evaluation of novel triazolyl p38α MAPK inhibitors with improved water solubility for formulation in cationic liposomes (SAINT-O-Somes) targeted at diseased endothelial cells is described. Water-solubilizing groups were introduced via a 'click' reaction of functional azides with 2-alkynyl imidazoles and isosteric oxazoles to generate two small libraries of 1,4-disubstituted 1,2,3-triazolyl p38α MAPK inhibitors. Triazoles with low IC50 values and desired physicochemical properties were screened for in vitro downregulation of proinflammatory gene expression and were formulated in SAINT-O-Somes. Triazolyl p38α MAPK inhibitor 88 (IC50=0.096 µM) displayed the most promising in vitro activity.