Anti-inflammatory effects of an optimized PPAR-γ agonist via NF-κB pathway inhibition

In our previous study, a PPAR-gamma agonist (+)-(R,E)-6a1 was elaborated as an anti-inflammatory lead. However, in silico analysis showed that (+ )-(R,E)-6a1 lacks key hydrogen bonding with Tyr(473) of PPAR-gamma LBD (ligand binding domain). To facilitate additional hydrogen bonding with Tyr(473), a more polar head group was introduced to the structure of (+)-(R,E)-6a1, and we also attempted to synthesize enzymatically stable derivatives. Of the synthetic derivatives, compound (+)-(R,E)-5f showed highest PPAR-gamma transcriptional activity and reasonable metabolic stability. Compound (+)-(R,E)-5f suppressed the expression of pro-inflammatory mediators such as inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), and tumor necrosis factor-alpha(TNF-alpha). Reduction of nitric oxide (NO), and ROS was also observed. Compound ( + )-(R,E)-5f was found to suppress the NF-kappa B pathway by inhibiting phosphorylation of IKK (I kappa B kinase), and this may lead to subsequent inhibition of I kappa B alpha (inhibitor of NF-kappa Ba) phosphorylation and inhibition of NF-kappa B activation. These results indicate that (+)-(R,E)-5f exerts anti-inflammatory activity via NF-KB pathway inhibition, and may serve as a potential anti-inflammatory lead.