Structure-based optimization of pyrazolo-pyrimidine and -pyridine inhibitors of PI3-kinase

Bioorg Med Chem Lett. 2010 Oct 15;20(20):6048-51. doi: 10.1016/j.bmcl.2010.08.067. Epub 2010 Aug 19.

Abstract

Starting from HTS hit 1a, X-ray co-crystallization and molecular modeling were used to design potent and selective inhibitors of PI3-kinase. Bioavailablity in this series was improved through careful modulation of physicochemical properties. Compound 12 displayed in vivo knockdown of PI3K pharmacodynamic markers such as pAKT, pPRAS40, and pS6RP in a PC3 prostate cancer xenograft model.

MeSH terms

  • Animals
  • Cell Line
  • Crystallography, X-Ray
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Prostatic Neoplasms / enzymology
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Rats
  • Solubility
  • Structure-Activity Relationship

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • pyridine