title: Identification of a selective thieno[2,3-c]pyridine inhibitor of COT kinase and TNF-alpha production.
abstract: 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.
authors.affiliation: Abbott Laboratories, Medicinal Chemistry, 100 Research Drive, Worcester, MA 01605, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Cusack
authors.forename: Hamish
authors.initials: H
authors.lastname: Allen
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bischoff
authors.forename: Anca
authors.initials: A
authors.lastname: Clabbers
authors.forename: Richard
authors.initials: R
authors.lastname: Dixon
authors.forename: Shannon
authors.initials: S
authors.lastname: Fix-Stenzel
authors.forename: Michael
authors.initials: M
authors.lastname: Friedman
authors.forename: Yvette
authors.initials: Y
authors.lastname: Gaumont
authors.forename: Dawn
authors.initials: D
authors.lastname: George
authors.forename: Thomas
authors.initials: T
authors.lastname: Gordon
authors.forename: Pintipa
authors.initials: P
authors.lastname: Grongsaard
authors.forename: Bernd
authors.initials: B
authors.lastname: Janssen
authors.forename: Yong
authors.initials: Y
authors.lastname: Jia
authors.forename: Maria
authors.initials: M
authors.lastname: Moskey
authors.forename: Christopher
authors.initials: C
authors.lastname: Quinn
authors.forename: Andres
authors.initials: A
authors.lastname: Salmeron
authors.forename: Christine
authors.initials: C
authors.lastname: Thomas
authors.forename: Grier
authors.initials: G
authors.lastname: Wallace
authors.forename: Neil
authors.initials: N
authors.lastname: Wishart
authors.forename: Zhengtian
authors.initials: Z
authors.lastname: Yu
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D053583:Interleukin-1beta / Q000378:metabolism; D008024:Ligands; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051379:Mice; D015394:Molecular Structure; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D008024:Ligands; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C446540:thienopyridine; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human