title: The development of monocyclic pyrazolone based cytokine synthesis inhibitors.
abstract: 4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.
authors.affiliation: Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd, Mason, OH 45040, USA. golebiowski.a@pg.com
authors.forename: Adam
authors.initials: A
authors.lastname: Golebiowski
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Townes
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Laufersweiler
authors.forename: Todd A
authors.initials: TA
authors.lastname: Brugel
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clark
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Clark
authors.forename: Jane F
authors.initials: JF
authors.lastname: Djung
authors.forename: Steven K
authors.initials: SK
authors.lastname: Laughlin
authors.forename: Mark P
authors.initials: MP
authors.lastname: Sabat
authors.forename: Roger G
authors.initials: RG
authors.lastname: Bookland
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: Michael J
authors.initials: MJ
authors.lastname: Janusz
authors.forename: Richard L
authors.initials: RL
authors.lastname: Walter
authors.forename: Mark E
authors.initials: ME
authors.lastname: Webster
authors.forename: Marlene J
authors.initials: MJ
authors.lastname: Mekel
mesh_terms: D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010003:Osteoarthritis / Q000517:prevention & control; D047069:Pyrazolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D047069:Pyrazolones; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases