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

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

  • Bioorg Med Chem Lett. 2014 Aug 1;24(15):3412-8. doi: 10.1016/j.bmcl.2014.05.080.
Jean-Paul G Seerden 1,  Gabriela Leusink-Ionescu 2,  Titia Woudenberg-Vrenken 3,  Bas Dros 2,  Grietje Molema 3,  Jan A A M Kamps 3,  Richard M Kellogg 2
Affiliations

Affiliations

  • 1 Syncom B.V., Kadijk 3, Groningen 9747 AT, The Netherlands. Electronic address: j.p.g.seerden@syncom.nl.
  • 2 Syncom B.V., Kadijk 3, Groningen 9747 AT, The Netherlands.
  • 3 Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
PMID: 24930833 DOI: 10.1016/j.bmcl.2014.05.080
Abstract

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.

Keywords

4-Fluorophenyl-imidazole; Alkyne-azide click reaction; Aqueous solubility; Multicomponent reactions; p38α MAPK, CK1δ, JAK2 inhibitors.

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