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

A new class of tumor necrosis factor alpha (TNF-α) 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-α production. X-ray co-crystallization studies with mutated p38α 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.

Graphical abstractA new class of tumor necrosis factor alpha (TNF-α) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N′-phenyl urea scaffold is described.Figure optionsDownload full-size imageDownload as PowerPoint slide