Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease

Pharmacological
inhibition of NLRP3 inflammasome activation may
offer a new option in the treatment of inflammatory bowel disease.
In this work, we report the design, synthesis, and 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 nontoxic, irreversible NLRP3 inhibitor able to decrease
interleukin-1β release from macrophages. Bioluminescence resonance
energy transfer experiments proved that this compound was able to
directly interfere with NLRP3 activation in cells. In vivo studies
confirmed the ability of the selected lead to alleviate the effects
of colitis induced by 2,4-dinitrobenzenesulfonic acid in rats after
oral administration.