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

Bioorg Med Chem Lett. 2014 Mar 1;24(5):1352-7. doi: 10.1016/j.bmcl.2014.01.034. Epub 2014 Jan 28.

Abstract

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

Keywords: COX-2, IL-6; Inflammation; Triazole; p38α MAPK inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / metabolism
  • Liposomes / chemistry
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Solubility
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry*
  • Triazoles / metabolism
  • Water / chemistry
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Imidazoles
  • Liposomes
  • Protein Kinase Inhibitors
  • Triazoles
  • Water
  • p38 Mitogen-Activated Protein Kinases