Syntheses and structure-activity relationships for some triazolyl p38 alpha 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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)

Abstract

The design, synthesis and biological evaluation of novel triazolyl p38 alpha 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 p38 alpha 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 p38 alpha MAPK inhibitor 88 (IC50 = 0.096 mu M) displayed the most promising in vitro activity. (C) 2014 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)1352-1357
Number of pages6
JournalBioorganic & Medicinal Chemistry Letters
Volume24
Issue number5
DOIs
Publication statusPublished - 1-Mar-2014

Keywords

  • p38 alpha MAPK inhibitors
  • Triazole
  • COX-2, IL-6
  • Inflammation
  • KINASE INHIBITORS
  • CLICK CHEMISTRY
  • PHYSICOCHEMICAL PROPERTIES
  • DIRECT ALKYNYLATION
  • ENDOTHELIAL-CELLS
  • IN-VITRO
  • POTENT
  • IMIDAZOLE
  • DESIGN
  • CYCLOADDITION

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