An SAR study that identified a series of thienopyridine-based potent IkappaB 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-kappaB reporter gene assay, demonstrating that they directly interfere with the NF-kappaB signaling pathway.