Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110alpha inhibitors

Bioorg Med Chem. 2007 Jan 1;15(1):403-12. doi: 10.1016/j.bmc.2006.09.047. Epub 2006 Oct 16.


3-{1-[(4-Fluorophenyl)sulfonyl]-1H-pyrazol-3-yl}-2-methylimidazo[1,2-a]pyridine, 2a, was discovered in our chemical library as a novel p110alpha inhibitor with an IC(50) of 0.67microM, through screening in a scintillation proximity assay. Optimization of the substituents of 2a increased the p110alpha inhibitory activity by more than 300-fold (2g: IC(50)=0.0018microM). Further structural modification of 2g afforded thiazole derivative 12, which has potent p110alpha inhibitory activity (IC(50) of 0.0028microM) and is highly selective for p110alpha over other PI3K isoforms. Compound 12 also inhibited serum-induced cell proliferation of A375 and HeLa cells in vitro with IC(50) values of 0.14microM and 0.21microM, respectively, and suppressed tumor growth by 37% in a mouse HeLa xenograft model when dosed intraperitoneally at 25mg/kg. These results suggest that selective p110alpha inhibitors may have potential as cancer therapeutic agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • HeLa Cells
  • Humans
  • Injections, Intraperitoneal
  • Isoenzymes / antagonists & inhibitors
  • Mice
  • Molecular Structure
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / administration & dosage
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Time Factors
  • Xenograft Model Antitumor Assays


  • Isoenzymes
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyridines
  • imidazo(1,2-a)pyridine