Inhibition of Tpl2 kinase and TNFalpha production with quinoline-3-carbonitriles for the treatment of rheumatoid arthritis.
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.
Hu
Yonghan
Y
Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. fhu@wyeth.com <fhu@wyeth.com>
Green
Neal
N
Gavrin
Lori K
LK
Janz
Kristin
K
Kaila
Neelu
N
Li
Huan-Qiu
HQ
Thomason
Jennifer R
JR
Cuozzo
John W
JW
Hall
J Perry
JP
Hsu
Sang
S
Nickerson-Nutter
Cheryl
C
Telliez
Jean-Baptiste
JB
Lin
Lih-Ling
LL
Tam
Steve
S
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*
D003432:Cross-Linking Reagents; D007093:Imidazoles; D009570:Nitriles; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; C029899:imidazole; C037219:quinoline; D020930:MAP Kinase Kinase Kinases