7-Phenyl-pyrido[2,3-d]pyrimidine-2,4-diamines: novel and highly selective protein tyrosine phosphatase 1B inhibitors

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7518-22. doi: 10.1016/j.bmcl.2012.10.035. Epub 2012 Oct 16.

Abstract

High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido[2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties.

MeSH terms

  • Animals
  • Diamines / chemical synthesis
  • Diamines / chemistry
  • Diamines / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • 7-phenyl-pyrido(2,3-d)pyrimidine-2,4-diamine
  • Diamines
  • Enzyme Inhibitors
  • Pyrimidines
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1