Synthesis of Acrylamide Analogs of Rimonabant and Evaluation of Anti-Inflammatory Activities by Inhibiting NF-κB and MAPK Signaling Pathways in Lipopolysaccharide-Induced BV2 Cells.

A series of acrylamide analogs of rimonabant, where the N-aminopiperidine moiety was replaced by various amines such as benzylamines or heterocyclic amines, were synthesized and their inhibition of nitric oxide (NO) production was evaluated in lipopolysaccharide (LPS)-induced BV2 microglial cells. Among the synthesized compounds, the 3-dimethylaminobenzyl analog 7n (IC50 = 1.32 ± 0.01 μM) showed significantly higher inhibitory activity than rimonabant (IC50 = 15.66 ± 0.14 μM) and suppressed NO production dose-dependently without cytotoxicity. In addition, 7n inhibited the expression of iNOS, COX-2, and proinflammatory cytokines and attenuated LPS-induced activation of nuclear factor-kappa B (NF-κB) and MAPK phosphorylation in BV2 cells. These results demonstrated that 7n exerted anti-inflammatory effects by NF-κB and the JNK and p38 MAPK pathways in BV2 cells and could become a prospective candidate for treatment of neuroinflammation-related disorders.