title: Inhibition of Tpl2 kinase and TNFalpha production with quinoline-3-carbonitriles for the treatment of rheumatoid arthritis.
abstract: The synthesis and structure-activity studies of a series of quinoline-3-carbonitriles as inhibitors of Tpl2 kinase are described. Potent inhibitors of Tpl2 kinase with selectivity against a panel of selected kinases in enzymatic assays and specificity in cell-based phosphorylation assays in LPS-treated human monocytes were identified. Selected inhibitors with moderate activity in human whole blood assay effectively inhibited LPS/D-Gal induced TNFalpha release when administered intraperitoneally in mice.
authors.affiliation: Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. fhu@wyeth.com <fhu@wyeth.com>
authors.forename: Yonghan
authors.initials: Y
authors.lastname: Hu
authors.forename: Neal
authors.initials: N
authors.lastname: Green
authors.forename: Lori K
authors.initials: LK
authors.lastname: Gavrin
authors.forename: Kristin
authors.initials: K
authors.lastname: Janz
authors.forename: Neelu
authors.initials: N
authors.lastname: Kaila
authors.forename: Huan-Qiu
authors.initials: HQ
authors.lastname: Li
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Thomason
authors.forename: John W
authors.initials: JW
authors.lastname: Cuozzo
authors.forename: J Perry
authors.initials: JP
authors.lastname: Hall
authors.forename: Sang
authors.initials: S
authors.lastname: Hsu
authors.forename: Cheryl
authors.initials: C
authors.lastname: Nickerson-Nutter
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Telliez
authors.forename: Lih-Ling
authors.initials: LL
authors.lastname: Lin
authors.forename: Steve
authors.initials: S
authors.lastname: Tam
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D003432:Cross-Linking Reagents; D007093:Imidazoles; D009570:Nitriles; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; C029899:imidazole; C037219:quinoline; D020930:MAP Kinase Kinase Kinases