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Inhibition of Tpl2 kinase and TNFα production with quinoline-3-carbonitriles for the treatment of rheumatoid arthritis

DOI: 10.1016/j.bmcl.2006.08.102
Title: Inhibition of Tpl2 kinase and TNFα production with quinoline-3-carbonitriles for the treatment of rheumatoid arthritis
Journal Title: Bioorganic & Medicinal Chemistry Letters
Volume: 16
Issue: 23
Publication Date: 1 December 2006
Start Page: 6067
End Page: 6072
Published online: online 14 September 2006
ISSN: 0960-894X
Affiliations:

  • a Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA

  • b Department of Inflammation, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA
  • Abstract: hesis 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 TNFα release when administered intraperitoneally in mice.
    Accepted: 28 August 2006
    Received: 28 July 2006
    Corresponding information:
    Tel: +1 617 665 5621
    Fax: +1 617 665 5682
    Email: fhu@wyeth.com

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