Discovery of 3,6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3,4-d]pyrimidines and 2-arylthieno[3,2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)

Bioorg Med Chem Lett. 2010 Jan 15;20(2):640-3. doi: 10.1016/j.bmcl.2009.11.050. Epub 2009 Dec 4.

Abstract

The morpholine hinge-region binding group on a series of pyrazolopyrimidine and thienopyrimidine mammalian target of rapamycin (mTOR) inhibitors was replaced with 3,6-dihydro-2H-pyran (DHP), giving compounds of equivalent potency and selectivity versus PI3K. These results establish the DHP group as a hinge-region binding motif for the preparation of highly potent and selective mTOR inhibitors.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Computer Simulation
  • Drug Discovery
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Microsomes / metabolism
  • Models, Molecular
  • Morpholines / chemistry*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Pyrans / chemistry*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • TOR Serine-Threonine Kinases

Substances

  • Intracellular Signaling Peptides and Proteins
  • Morpholines
  • Pyrans
  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • pyrazolopyridine
  • thienopyrimidine
  • morpholine
  • Adenosine Triphosphate
  • mTOR protein, mouse
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases