Osteoarthritis Research Today is a free monthly online journal that collates and summarizes the latest research about Osteoarthritis, including details on treatment, symptoms, causes, medication.

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

Maier JA, Brugel TA, Clark MP, Sabat M, Golebiowski A, Bookland RG, Laufersweiler MJ, Laughlin SK, Vanrens JC, De B, Hsieh LC, Brown KK, Juergens K, Walter RL, Janusz MJ

Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd., Mason, OH 45040, USA.

A new class of tumor necrosis factor alpha (TNF-alpha) 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-alpha 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 p38alpha 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.

Published 1 June 2006 in Bioorg Med Chem Lett, 16(13): 3514-8.
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