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

Jean-Paul G Seerden,Gabriela Leusink-Ionescu,Robin Leguijt,Catherine Saccavini,Edith Gelens,Bas Dros,Titia Woudenberg-Vrenken,Grietje Molema,Jan A A M Kamps,Richard M Kellogg

Bioorganic & Medicinal Chemistry Letters（2014）

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摘要

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=0.096μM) displayed the most promising in vitro activity.

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