Development of an Acrylate Derivative Targeting the NLRP3 Inflam- masome for the Treatment of Inflammatory Bowel Disease

Abstract

Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of Inflamma- tory Bowel Disease (IBD). In this work, we report the design, the synthesis, and the biological screening of a series of acrylate derivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptotic properties allowed the selection of 11 (INF39), a stable, non toxic compound inhibiting interleukin 1β release from macrophages. Bioluminescence resonance energy transfer experiments proved that this compound was able to directly interfere with NLRP3 acti- vation in cells. In vivo studies confirmed the ability of the selected lead to alleviate the effects of DNBS-induced colitis in rats after oral administration.