Design and synthesis of a novel pyrrolidinyl pyrido pyrimidinone derivative as a potent inhibitor of PI3Kα and mTOR

Bioorg Med Chem Lett. 2012 Aug 1;22(15):5098-103. doi: 10.1016/j.bmcl.2012.05.100. Epub 2012 Jun 6.

Abstract

Lead optimization efforts that employed structure base drug design and physicochemical property based optimization leading to the discovery of a novel series of 4-methylpyrido pyrimidinone (MPP) are discussed. Synthesis and profile of 1, a PI3Kα/mTOR dual inhibitor, is highlighted.

MeSH terms

  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design*
  • Half-Life
  • Humans
  • 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
  • Pyridones / chemical synthesis
  • Pyridones / chemistry*
  • Pyridones / pharmacokinetics
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / chemistry*
  • Pyrimidinones / pharmacokinetics
  • Pyrrolidines / chemistry
  • Rats
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidines
  • Pyrimidinones
  • Pyrrolidines
  • TOR Serine-Threonine Kinases
  • pyrrolidine