title: Discovery and structure-activity relationship of coumarin derivatives as TNF-alpha inhibitors.
abstract: The discovery and structure-activity relationship of a novel series of coumarin-based TNF-alpha inhibitors is described. Starting from the initial lead 1a, various derivatives were prepared surrounding the coumarin core structure to optimize the in vitro inhibitory activity of TNF-alpha production by human peripheral blood mononuclear cells (hPBMC), stimulated by bacterial lipopolysaccharide (LPS). Selected compounds also demonstrated in vivo inhibition of TNF-alpha production in rats.
authors.affiliation: Department of Chemistry, Chugai Pharma USA LLC, 6275 Nancy Ridge Drive, San Diego, CA 92121, USA. jcheng@trlusa.com
authors.forename: Jie-Fei
authors.initials: JF
authors.lastname: Cheng
authors.forename: Mi
authors.initials: M
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Wallace
authors.forename: Sovouthy
authors.initials: S
authors.lastname: Tith
authors.forename: Thomas
authors.initials: T
authors.lastname: Arrhenius
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kashiwagi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ono
authors.forename: Akira
authors.initials: A
authors.lastname: Ishikawa
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sato
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kozono
authors.forename: Hediki
authors.initials: H
authors.lastname: Sato
authors.forename: Alex M
authors.initials: AM
authors.lastname: Nadzan
mesh_terms: D002478:Cells, Cultured; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D003374:Coumarins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C030123:coumarin