Novel anti-inflammatory agents targeting CXCR4: Design, synthesis, biological evaluation and preliminary pharmacokinetic study

CXCR4 plays a crucial role in the inflammatory disease process, providing an attractive means for drug targeting. A series of novel amide-sulfamide derivatives were designed, synthesized and comprehensively evaluated. This new scaffold exhibited much more potent CXCR4 inhibitory activity, with more than 70% of the compounds showed notably better binding affinity than the reference drug AMD3100 in the binding assay. Additionally, in the Matrigel invasion assay, most of our compounds significantly blocked the tumor cell invasion, demonstrating superior efficacy compared to AMD3100. Furthermore, compound IIj blocked mice ear inflammation by 75% and attenuated ear edema and damage substantially in an in vivo model of inflammation. Western blot analyses revealed that CXCR4 modulator IIj significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt. Moreover, compound IIj had no observable cytotoxicity and displayed a favourable plasma stability in our preliminary pharmacokinetic study. The preliminary structure-activity relationships were also summarized. In short, this novel amide-sulfamide scaffold exhibited potent CXCR4 inhibitory activity both in vitro and in vivo. These results also confirmed that developing modulators targeting CXCR4 provides an exciting avenue for treatment of inflammation. [Display omitted] •A series of amide-sulfamide compounds targeting CXCR4 were designed and synthesized.•Most of the compounds showed potent in vitro CXCR4 inhibitory activity.•Compound IIj significantly attenuated mouse ear inflammation by 75%.•IIj significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt.•IIj displayed a favourable plasma stability in our primary pharmacokinetic study.