| Literature DB >> 19716697 |
Jiang-Ping Wu1, Roman Fleck, Janice Brickwood, Alison Capolino, Katrina Catron, Zhidong Chen, Charles Cywin, Jonathan Emeigh, Melissa Foerst, John Ginn, Matt Hrapchak, Eugene Hickey, Ming-Hong Hao, Mohammed Kashem, Jun Li, Weimin Liu, Tina Morwick, Richard Nelson, Daniel Marshall, Leslie Martin, Peter Nemoto, Ian Potocki, Michel Liuzzi, Gregory W Peet, Erika Scouten, David Stefany, Michael Turner, Steve Weldon, Clare Zimmitti, Denise Spero, Terence A Kelly.
Abstract
An SAR study that identified a series of thienopyridine-based potent IkappaB Kinase beta (IKKbeta) inhibitors is described. With focuses on the structural optimization at C4 and C6 of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred at C4, whereas polar groups with proper orientation at C6 efficiently enhance compound potency. The most potent analogues inhibit IKKbeta with IC50s 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-kappaB reporter gene assay, demonstrating that they directly interfere with the NF-kappaB signaling pathway.Entities:
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Year: 2009 PMID： 19716697 DOI： 10.1016/j.bmcl.2009.08.054
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823