Optimization and biological evaluation of aminopyrimidine-based IκB kinase β inhibitors with potent anti-inflammatory effects

Abstract

Targeting IκB kinase β (IKKβ) can be a promising strategy in the development of a therapeutic treatment of inflammatory diseases because IKKβ is well-recognized as a key mediator of the NF-κB signaling pathway. In this study, we have successfully developed a structure-activity relationship (SAR) profile of the aminopyrimidine-based IKKβ inhibitors through the structure-based design strategy to improve the physicochemical properties and cellular activity in terms of the anti-inflammatory effects. Representative compounds exhibited desirable activity in nitric oxide (NO) reduction by inhibiting the synthesis of inducible nitric oxide synthase (iNOS), and strongly inhibited the expression of pro-inflammatory cytokines (IL-1α, IL-6, and TNF-α). The inhibitory effects of 8e on the phosphorylation in the NF-κB pathway further supported that the suppression of the NF-κB signaling pathway induced the anti-inflammatory effect in LPS-stimulated Raw 264.7 cells. © 2016 Elsevier Masson SAS.