Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors

Bioorg Med Chem Lett. 2009 Apr 15;19(8):2244-8. doi: 10.1016/j.bmcl.2009.02.094. Epub 2009 Feb 27.

Abstract

A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3beta.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Drug Discovery* / methods
  • Humans
  • Mice
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology*
  • Thienopyridines
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology

Substances

  • 5-pyrrolopyridinyl-2-thiophenecarboxamide
  • Protein Kinase Inhibitors
  • Pyridines
  • Thienopyridines
  • Thiophenes
  • AKT2 protein, human
  • Proto-Oncogene Proteins c-akt