Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 1-substituent

Bioorg Med Chem Lett. 2010 Feb 15;20(4):1440-4. doi: 10.1016/j.bmcl.2009.12.086. Epub 2010 Jan 4.

Abstract

A series of pyrazolopyrimidine mammalian Target Of Rapamycin (mTOR) inhibitors with various substituents at the 1-position have been prepared, resulting in compounds with excellent potency, selectivity and microsomal stability. Combination of a 1-cyclohexyl ketal group with a 2,6-ethylene bridged morpholine in the 4-position and a ureidophenyl group in the 6-positon resulted in compound 8a, that selectively suppressed key mTOR biomarkers in vivo for at least 8h following iv administration and showed excellent oral activity in a xenograft tumor model.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism*
  • Administration, Oral
  • Animals
  • Binding, Competitive
  • Drug Stability
  • Humans
  • Inhibitory Concentration 50
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Microsomes / enzymology
  • Molecular Structure
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein Serine-Threonine Kinases / metabolism
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases
  • Xenograft Model Antitumor Assays

Substances

  • Intracellular Signaling Peptides and Proteins
  • Pyrazoles
  • Pyridines
  • pyrazolopyridine
  • Adenosine Triphosphate
  • MTOR protein, human
  • mTOR protein, mouse
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases