Novel azulene-based derivatives as potent multi-receptor tyrosine kinase inhibitors

Bioorg Med Chem Lett. 2010 Oct 15;20(20):6129-32. doi: 10.1016/j.bmcl.2010.08.025. Epub 2010 Aug 10.

Abstract

A series of azulene-based derivatives were synthesized as potent inhibitors for receptor tyrosine kinases such as FMS-like tyrosine kinase 3 (FLT-3). Systematic side chain modification of prototype 1a was carried out through SAR studies. Analogue 22 was identified from this series and found to be one of the most potent FLT-3 inhibitors, with good pharmaceutical properties, superior efficacy, and tolerability in a tumor xenograft model.

MeSH terms

  • Animals
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Azulenes / blood
  • Azulenes / chemistry*
  • Azulenes / pharmacology
  • Azulenes / therapeutic use*
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Rats
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • Azulenes
  • azulene
  • Receptor Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3