title: 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.
abstract: 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.
authors.affiliation: Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd., Mason, OH 45040, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Maier
authors.forename: Todd A
authors.initials: TA
authors.lastname: Brugel
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clark
authors.forename: Mark
authors.initials: M
authors.lastname: Sabat
authors.forename: Adam
authors.initials: A
authors.lastname: Golebiowski
authors.forename: Roger G
authors.initials: RG
authors.lastname: Bookland
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Laufersweiler
authors.forename: Steven K
authors.initials: SK
authors.lastname: Laughlin
authors.forename: John C
authors.initials: JC
authors.lastname: Vanrens
authors.forename: Biswanath
authors.initials: B
authors.lastname: De
authors.forename: Lily C
authors.initials: LC
authors.lastname: Hsieh
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Brown
authors.forename: Karen
authors.initials: K
authors.lastname: Juergens
authors.forename: Richard L
authors.initials: RL
authors.lastname: Walter
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Janusz
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006860:Hydrogen Bonding; D007461:Iodoacetates; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D010003:Osteoarthritis / Q000139:chemically induced / Q000188:drug therapy*; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007461:Iodoacetates; D008070:Lipopolysaccharides; D010671:Phenylurea Compounds; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate