title: The development of new bicyclic pyrazole-based cytokine synthesis inhibitors.
abstract: 4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.
authors.affiliation: Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd, Mason, OH 45040, USA. townes.ja@pg.com
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Townes
authors.forename: Adam
authors.initials: A
authors.lastname: Golebiowski
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clark
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Laufersweiler
authors.forename: Todd A
authors.initials: TA
authors.lastname: Brugel
authors.forename: Mark
authors.initials: M
authors.lastname: Sabat
authors.forename: Roger G
authors.initials: RG
authors.lastname: Bookland
authors.forename: Steve 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: Susan C
authors.initials: SC
authors.lastname: Xu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Janusz
authors.forename: Richard L
authors.initials: RL
authors.lastname: Walter
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases