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

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Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125 Torino, Italy
Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy
§ Faculty of Biology, Medicine and Health, The University of Manchester, R4.004 AV Hill Building, Oxford Road, Manchester, U.K.
Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital “Virgen de la Arrixaca”, University of Murcia, Carretera Buenavista s/n, 30120, El Palmar, Murcia, Spain
Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
# Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy
*P.P.: e-mail, [email protected]; phone, +34 868885038.
*M.B.: e-mail, [email protected]; phone, +39 011 6707667.
Cite this: J. Med. Chem. 2017, 60, 9, 3656–3671
Publication Date (Web):April 14, 2017
Copyright © 2017 American Chemical Society

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    Abstract Image

    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.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b01624.

    • Structures of NLRP3 pathway inhibitors studied in IBD models and relevant references, reactivity of 11 with cysteamine, stability of 11 in human serum, BRET assay approach, table of criteria used for scoring of colonic macroscopic damage, and damage-score determination in 11-treated animals (PDF)

    • Molecular formula strings (CSV)

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