Discovery and Optimization of Potent and Selective Imidazopyridine and Imidazopyridazine mTOR Inhibitors

Bioorg Med Chem Lett. 2012 Aug 1;22(15):4967-74. doi: 10.1016/j.bmcl.2012.06.033. Epub 2012 Jun 16.

Abstract

mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.

MeSH terms

  • Animals
  • Benzimidazoles / chemistry
  • Binding Sites
  • Binding, Competitive
  • Crystallography, X-Ray
  • Drug Design
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Imidazoles / chemistry
  • Male
  • Mice
  • Microsomes, Liver / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Structure, Tertiary
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry*
  • Pyridazines / pharmacokinetics
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Benzimidazoles
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyridazines
  • Pyridines
  • pyridazine
  • imidazole
  • benzimidazole
  • TOR Serine-Threonine Kinases
  • pyridine