Discovery of dibenzyl amide derivatives as novel CXCR4 modulators against inflammatory bowel disease

• DOI: 10.1016/j.ejmcr.2024.100134
• Publication Date: 2024-01-23T13:15:57Z
• Authors: Xiaoying Jiang; Liuxin Lu; Jiahui Wang; Meng Yu; Rui Wu; Rui Zhao; Hao Wen; Renren Bai
• Keywords: RS1-441; Dibenzyl amide derivatives; Anti-inflammatory activity; Other systems of medicine; 0303 health sciences; 03 medical and health sciences; Pharmacy and materia medica; CXCR4 modulators; Inflammatory bowel disease (IBD); RZ201-999

The CXCR4/CXCL12 chemokine axis demonstrates significant potential in the treatment of inflammatory bowel disease (IBD) due to its crucial roles and immune responses. Modulating pathway can be an effective therapeutic approach ameliorate state IBD. In this study, a novel series meta-dibenzyl amide derivatives were designed synthesized based on lead compound AMD3100 structurally modified derivatives. Both vitro vivo assays conclusively established that these compounds exhibited potent CXCR4 antagonism anti-inflammatory activity. Compound 5t demonstrated superior inhibitory rates binding affinity chemotaxis CXCR4+ cells compared AMD3100. Furthermore, notably reduced swelling volume tissue thickness carrageenan-induced mouse paw edema model. Most importantly, dextran sodium sulfate (DSS)-induced colitis model, significantly mitigated colonic inflammation both macroscopic microscopic levels, while suppressing expression factors myeloperoxidase (MPO). These findings unequivocally establish immense