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

A new class of tumor necrosis factor alpha (TNF-α) synthesis inhibitors based on a N-2,4-pyrimidine-N-phenyl-N′-alkyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-α production. Two analogs were tested in an in vivo rat iodoacetate model of osteoarthritis and shown to be orally efficacious. 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.