The discovery of thienopyridine analogues as potent IκB kinase β inhibitors. Part II

An SAR study that identified a series of thienopyridine-based potent IκB Kinase β (IKKβ inhibitors is described. An SAR study that identified a series of thienopyridine-based potent IκB Kinase β (IKKβ) inhibitors is described. With focuses on the structural optimization at C 4 and C 6 of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred at C 4 , whereas polar groups with proper orientation at C 6 efficiently enhance compound potency. The most potent analogues inhibit IKKβ with IC 50 s as low as 40 nM, suppress LPS-induced TNF-α production in vitro and in vivo, display good kinase selectivity profiles, and are active in a HeLa cell NF-κB reporter gene assay, demonstrating that they directly interfere with the NF-κB signaling pathway.