Highly potent aminopyridines as Syk kinase inhibitors

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5419-23. doi: 10.1016/j.bmcl.2012.07.045. Epub 2012 Jul 20.

Abstract

A novel class of potent Syk inhibitors has been developed from rational design. Highly potent aminopyridine derivatives bearing a 4-trifluoromethyl-2-pyridyl motif and represented by compound 13b IC(50): 0.6 nM were identified. Substitution by a 2-pyrazinyl motif and SAR expansion in position 4 of the central core provided diverse potent non-cytotoxic Syk inhibitors showing nanomolar activity inhibiting human mast cell line LAD2 degranulation.

MeSH terms

  • Aminopyridines / chemistry*
  • Aminopyridines / pharmacology*
  • Binding Sites
  • Cell Degranulation / drug effects
  • Cell Line
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mast Cells / drug effects*
  • Mast Cells / enzymology
  • Mast Cells / physiology
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / metabolism
  • Syk Kinase

Substances

  • Aminopyridines
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase