Discovery and structure-activity relationship of coumarin derivatives as TNF-alpha inhibitors.
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.
Cheng
Jie-Fei
JF
Department of Chemistry, Chugai Pharma USA LLC, 6275 Nancy Ridge Drive, San Diego, CA 92121, USA. jcheng@trlusa.com
Chen
Mi
M
Wallace
David
D
Tith
Sovouthy
S
Arrhenius
Thomas
T
Kashiwagi
Hirotaka
H
Ono
Yoshiyuki
Y
Ishikawa
Akira
A
Sato
Haruhiko
H
Kozono
Toshiro
T
Sato
Hediki
H
Nadzan
Alex M
AM
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
D003374:Coumarins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C030123:coumarin