Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors

Bioorg Med Chem Lett. 2010 Dec 1;20(23):7037-41. doi: 10.1016/j.bmcl.2010.09.112. Epub 2010 Sep 29.


Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.

MeSH terms

  • Animals
  • Binding Sites
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Male
  • Mice
  • Prostatic Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship
  • Tumor Burden / drug effects


  • Protein Kinase Inhibitors
  • Pyrimidines
  • Proto-Oncogene Proteins c-akt