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doi:10.1016/j.bmcl.2006.03.096 
Copyright © 2006 Elsevier Ltd All rights reserved.
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
Jennifer A. Maier, Todd A. Brugel
, 
, Michael P. Clark, Mark Sabat, Adam Golebiowski, Roger G. Bookland, Matthew J. Laufersweiler, Steven K. Laughlin, John C. VanRens, Biswanath De, Lily C. Hsieh, Kimberly K. Brown, Karen Juergens, Richard L. Walter and Michael J. Janusz
Received 10 March 2006;
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Abstract
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 abstract
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.
Keywords: Cytokine synthesis inhibitors; p38α kinase; Urea
