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. Epub 2014 Jun 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Casein Kinase Idelta / antagonists & inhibitors*
  • Casein Kinase Idelta / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / metabolism
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • Imidazoles
  • Protein Kinase Inhibitors
  • Triazoles
  • JAK2 protein, human
  • Janus Kinase 2
  • Casein Kinase Idelta
  • Mitogen-Activated Protein Kinases