Discovery and optimization of potent and selective benzonaphthyridinone analogs as small molecule mTOR inhibitors with improved mouse microsome stability

Bioorg Med Chem Lett. 2011 Jul 1;21(13):4036-40. doi: 10.1016/j.bmcl.2011.04.129. Epub 2011 May 7.

Abstract

Starting from small molecule mTOR inhibitor Torin1, replacement of the piperazine ring with a phenyl ring resulted in a new series of mTOR inhibitors (as exemplified by 10) that showed superior potency and selectivity for mTOR, along with significantly improved mouse liver microsome stability and a longer in vivo half-life.

MeSH terms

  • Animals
  • Cells, Cultured
  • Drug Discovery*
  • Drug Stability
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Inhibitory Concentration 50
  • Mice
  • Microsomes, Liver / drug effects*
  • Molecular Structure
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

  • 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
  • Enzyme Inhibitors
  • Naphthyridines
  • TOR Serine-Threonine Kinases