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. 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 IKKβ with IC₅₀s 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.