Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1377231 | Bioorganic & Medicinal Chemistry Letters | 2006 | 5 Pages |
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.
Graphical abstractA new class of tumor necrosis factor alpha (TNF-α) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N′-alkyl urea scaffold is described.Figure optionsDownload full-size imageDownload as PowerPoint slide