title: The development of novel inhibitors of tumor necrosis factor-alpha (TNF-alpha) production based on substituted [5,5]-bicyclic pyrazolones.
abstract: Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-alpha production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.
authors.affiliation: Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd, Mason, OH 45040, USA. laufersweiler.mj@pg.com
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: Adam
authors.initials: A
authors.lastname: Golebiowski
authors.forename: Roger G
authors.initials: RG
authors.lastname: Bookland
authors.forename: Steven K
authors.initials: SK
authors.lastname: Laughlin
authors.forename: Mark P
authors.initials: MP
authors.lastname: Sabat
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Townes
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: Sandra A
authors.initials: SA
authors.lastname: Heitmeyer
authors.forename: Karen
authors.initials: K
authors.lastname: Juergens
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Brown
authors.forename: Marlene J
authors.initials: MJ
authors.lastname: Mekel
authors.forename: Richard L
authors.initials: RL
authors.lastname: Walter
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Janusz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D008070:Lipopolysaccharides / Q000494:pharmacology; D008958:Models, Molecular; D047069:Pyrazolones / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D008070:Lipopolysaccharides; D047069:Pyrazolones; D014409:Tumor Necrosis Factor-alpha