Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: synthesis and SAR studies

Bioorg Med Chem Lett. 2006 Aug 15;16(16):4163-8. doi: 10.1016/j.bmcl.2006.05.092. Epub 2006 Jun 9.


A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. SAR studies resulted in potent inhibitors of AKT with IC(50) values as low as single digit nanomolar as represented by compound 2aa. Compound 2aa showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determined and discussed.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Chemistry, Pharmaceutical / methods*
  • Crystallization
  • Crystallography, X-Ray
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Models, Chemical
  • Models, Molecular
  • Protein Binding
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry*


  • Enzyme Inhibitors
  • Thiophenes
  • Proto-Oncogene Proteins c-akt