The discovery of thienopyridine analogues as potent I[kappa]B kinase beta inhibitors. Part II

An SAR study that identified a series of thienopyridine-based potent I[kappa]B Kinase beta (IKK beta ) inhibitors is described. With focuses on the structural optimization at C sub(4) and C sub(6) of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred a...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-10, Vol.19 (19), p.5547-5551
Main Authors: Wu, Jiang-Ping, Fleck, Roman, Brickwood, Janice, Capolino, Alison, Catron, Katrina, Chen, Zhidong, Cywin, Charles, Emeigh, Jonathan, Foerst, Melissa, Ginn, John, Hrapchak, Matt, Hickey, Eugene, Hao, Ming-Hong, Kashem, Mohammed, Li, Jun, Liu, Weimin, Morwick, Tina, Nelson, Richard, Marshall, Daniel, Martin, Leslie, Nemoto, Peter, Potocki, Ian, Liuzzi, Michel, Peet, Gregory W, Scouten, Erika, Stefany, David, Turner, Michael, Weldon, Steve, Zimmitti, Clare, Spero, Denise, Kelly, Terence A
Format: Article
Language:English
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Summary:An SAR study that identified a series of thienopyridine-based potent I[kappa]B Kinase beta (IKK beta ) inhibitors is described. With focuses on the structural optimization at C sub(4) and C sub(6) of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred at C sub(4), whereas polar groups with proper orientation at C sub(6) efficiently enhance compound potency. The most potent analogues inhibit IKK beta with IC sub(50)s as low as 40 nM, suppress LPS-induced TNF- alpha production in vitro and in vivo, display good kinase selectivity profiles, and are active in a HeLa cell NF-[kappa]B reporter gene assay, demonstrating that they directly interfere with the NF-[kappa]B signaling pathway.
ISSN:0960-894X
DOI:10.1016/j.bmcl.2009.08.054