Synthesis and structure-activity relationships of 4-fluorophenyl-imidazole p38 alpha MAPK, CK1 delta and JAK2 kinase inhibitors

Jean-Paul G. Seerden*, Gabriela Leusink-Ionescu, Titia Woudenberg - Vrenken, Bas Dros, Grietje Molema, Jan A. A. M. Kamps, Richard M. Kellogg

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)

Abstract

The synthesis and structure-activity relationships of novel 4-(4 '-fluorophenyl)imidazoles as selective p38 alpha MAPK, CK1 delta 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 p38 alpha MAPK with IC50 = 250 nM and 96 nM, respectively. Pyridine 3 gave CK1 delta inhibition with IC50 = 89 nM and pyridin-2-one 31 gave JAK2 inhibition with IC50 = 62 nM. (C) 2014 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)3412-3418
Number of pages7
JournalBioorganic & Medicinal Chemistry Letters
Volume24
Issue number15
DOIs
Publication statusPublished - 1-Aug-2014

Keywords

  • p38 alpha MAPK, CK1 delta, JAK2 inhibitors
  • 4-Fluorophenyl-imidazole
  • Multicomponent reactions
  • Alkyne-azide click reaction
  • Aqueous solubility
  • ACTIVATED PROTEIN-KINASE
  • SAINT-O-SOMES
  • ENDOTHELIAL-CELLS
  • IN-VIVO
  • POTENT
  • DISCOVERY
  • ANTI-VCAM-1
  • SELECTIVITY
  • IMIDAZOLES
  • EFFICIENCY

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