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

• Published in: Bioorganic & medicinal chemistry letters 2006-07, Vol.16 (13), p.3514-3518
• Main Authors: Maier, Jennifer A., Brugel, Todd A., Clark, Michael P., Sabat, Mark, Golebiowski, Adam, Bookland, Roger G., Laufersweiler, Matthew J., Laughlin, Steven K., VanRens, John C., De, Biswanath, Hsieh, Lily C., Brown, Kimberly K., Juergens, Karen, Walter, Richard L., Janusz, Michael J.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - chemistry; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - classification; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Arthritis, Experimental - chemically induced; Arthritis, Experimental - drug therapy; Binding Sites; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Crystallography, X-Ray; Cytokine synthesis inhibitors; Disease Models, Animal; Drug Evaluation, Preclinical; Hydrogen Bonding; Iodoacetates; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Medical sciences; Models, Molecular; Molecular Structure; Osteoarthritis - chemically induced; Osteoarthritis - drug therapy; p38α kinase; Pharmacology. Drug treatments; Phenylurea Compounds - chemistry; Phenylurea Compounds - classification; Phenylurea Compounds - pharmacology; Pyrimidines - chemistry; Pyrimidines - classification; Pyrimidines - pharmacology; Rats; Stereoisomerism; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis; Urea
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.03.096

A 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. 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.