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

Mattia Cocco, Carolina Pellegrini, Helios Martínez Banaclocha, Marta Giorgis, Elisabetta Marini, Annalisa Costale, Gianluca Miglio, Matteo Fornai, Luca Antonioli, Gloria Lopez-Castejon, Ana Tapia-Abellan, Diego Angosto, Iva Hafner-Bratkovi, Luca Regazzoni, Corrado Blandizzi , Pablo Pelegrin, Massimo Bertinaria

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Abstract

Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of Inflammatory
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 non-toxic, 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 DNBSinduced
colitis in rats after oral administration
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume60
Issue number9
Early online date14 Apr 2017
DOIs
Publication statusPublished - 2017

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