Discovery of 2-ureidophenyltriazines bearing bridged morpholines as potent and selective ATP-competitive mTOR inhibitors

Bioorg Med Chem Lett. 2010 Apr 15;20(8):2644-7. doi: 10.1016/j.bmcl.2010.02.045. Epub 2010 Feb 13.

Abstract

Incorporation of bridged morpholines in monocyclic triazine PI3K/mTOR inhibitors gave compounds with increased mTOR selectivity relative to the corresponding morpholine analogs. Compounds with ureidophenyl groups gave highly potent and selective mTOR inhibitors. Potency and selectivity was demonstrated both in vitro and in vivo through biomarker suppression studies. Select compounds exhibited potent inhibition of tumor growth in nude mouse xenograft assays upon PO and IV administration.

MeSH terms

  • Adenosine Triphosphate / chemistry*
  • Animals
  • Drug Discovery
  • Inhibitory Concentration 50
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Mice
  • Mice, Nude
  • Morpholines / chemistry*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases
  • Triazines / chemistry*
  • Triazines / pharmacology*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Morpholines
  • Triazines
  • Adenosine Triphosphate
  • mTOR protein, mouse
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases