N-Phenyl-N-purin-6-yl ureas: the design and synthesis of p38alpha MAP kinase inhibitors

Bioorg Med Chem Lett. 2003 Mar 24;13(6):1191-4. doi: 10.1016/s0960-894x(03)00048-9.

Abstract

The design, synthesis and SAR of a series of 2,6,9-trisubstituted purine inhibitors of p38alpha kinase is reported. Synthetic routes were devised to allow for array synthesis in which all three points of diversity could be facilely explored. The binding of this novel series to p38alpha kinase, which was predicted to have several key interactions in common with SB-203580, was confirmed by X-ray crystallography of 19 (p38 IC(50)=82 nM).

MeSH terms

  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Indicators and Reagents
  • Magnetic Resonance Spectroscopy
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Conformation
  • Structure-Activity Relationship
  • Urea / analogs & derivatives
  • Urea / chemical synthesis*
  • Urea / pharmacology*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Enzyme Inhibitors
  • Indicators and Reagents
  • N-phenyl-N-purin-6-yl urea
  • Urea
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases