Identification of a selective thieno[2,3-c]pyridine inhibitor of COT kinase and TNF-alpha production

• Published in: Bioorganic & medicinal chemistry letters 2009-03, Vol.19 (6), p.1722-1725
• Main Authors: Cusack, Kevin, Allen, Hamish, Bischoff, Agnieszka, Clabbers, Anca, Dixon, Richard, Fix-Stenzel, Shannon, Friedman, Michael, Gaumont, Yvette, George, Dawn, Gordon, Thomas, Grongsaard, Pintipa, Janssen, Bernd, Jia, Yong, Moskey, Maria, Quinn, Christopher, Salmeron, Andres, Thomas, Christine, Wallace, Grier, Wishart, Neil, Yu, Zhengtian
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Rheumatoid - drug therapy; Chemistry, Pharmaceutical - methods; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Extracellular Signal-Regulated MAP Kinases - metabolism; Humans; Hydrogen Bonding; Inhibitory Concentration 50; Interleukin-1beta - metabolism; Ligands; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - chemistry; Mice; Molecular Structure; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - chemistry; Pyridines - chemical synthesis; Pyridines - pharmacology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - chemistry; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.01.088

COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-alpha and other pro-inflammatory cytokines such as IL-1beta via the ERK/MAP kinase pathway. As TNF-alpha and IL-1beta are clinically validated targets for therapeutic intervention in rheumatoid arthritis (RA), blocking COT provides a potential avenue for amelioration of disease. Herein we describe identification of a cellular active selective small molecule inhibitor of COT kinase.