Discovery and structure-activity relationship of coumarin derivatives as TNF-alpha inhibitors |
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| Authors: | Cheng Jie-Fei Chen Mi Wallace David Tith Sovouthy Arrhenius Thomas Kashiwagi Hirotaka Ono Yoshiyuki Ishikawa Akira Sato Haruhiko Kozono Toshiro Sato Hediki Nadzan Alex M |
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| Institution: | Department of Chemistry, Chugai Pharma USA LLC, 6275 Nancy Ridge Drive, San Diego, CA 92121, USA. jcheng@trlusa.com |
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| 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. |
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