Development of N-2,4-pyrimidine-N-phenyl-N'-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-alpha) synthesis. Part 1

Bioorg Med Chem Lett. 2006 Jul 1;16(13):3510-3. doi: 10.1016/j.bmcl.2006.03.095. Epub 2006 May 2.

Abstract

A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Binding Sites
  • Crystallography, X-Ray
  • Hydrogen Bonding
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Models, Molecular
  • Molecular Structure
  • Phenylurea Compounds / chemistry*
  • Phenylurea Compounds / classification
  • Phenylurea Compounds / pharmacology*
  • Pyrimidines / chemistry*
  • Pyrimidines / classification
  • Pyrimidines / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Lipopolysaccharides
  • Phenylurea Compounds
  • Pyrimidines
  • Tumor Necrosis Factor-alpha
  • Adenosine Triphosphate