Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors

Bioorg Med Chem Lett. 2016 Apr 15;26(8):2065-7. doi: 10.1016/j.bmcl.2016.02.074. Epub 2016 Feb 26.

Abstract

We report structure-guided modifications of the benzyloxy substituent of the Insulin-like Growth Factor-1 Receptor (IGF-1R) inhibitor NVP-AEW541. This chemical group has been shown to confer selectivity against other protein kinases but at the expense of a metabolism liability. X-ray crystallography has revealed that the benzyloxy moiety interacts with a lysine cation of the IGF-1R kinase domain via its ether function and its aromatic π-system and is nicely embedded in an induced hydrophobic pocket. We show that 1,4-diethers displaying an adequate hydrophobic and constrained shape are advantageous benzyloxy replacements. A single digit nanomolar inhibitor (compound 20, IC50=8.9 nM) was identified following this approach.

Keywords: IGF-1R X-ray co-crystal structure; IGF-1R inhibitor; Structure-guided design.

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Humans
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptor, IGF Type 1 / metabolism
  • Structure-Activity Relationship

Substances

  • 5-(3-phenyl-(2-cyclic-ether)-methylether)-4-aminopyrrolo(2,3-d)pyrimidine
  • NVP-AEW541
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • Receptor, IGF Type 1