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

被引：174

作者：

Cocco, Mattia ^{[1
]}

Pellegrini, Carolina ^{[2
,3
]}

Martinez-Banadocha, Helios ^{[4
]}

Giorgis, Marta ^{[1
]}

Marini, Elisabetta ^{[1
]}

Costale, Annalisa ^{[1
]}

Miglio, Gianluca ^{[1
]}

Fomai, Matteo ^{[2
]}

Antonioli, Luca ^{[2
]}

Lopez-Castejon, Gloria ^{[3
]}

Tapia-Abellan, Ana ^{[4
]}

Angosto, Diego ^{[4
]}

Hafner-Bratkovic, Iva ^{[5
]}

Regazzoni, Luca ^{[6
]}

Blandizzi, Corrado ^{[2
]}

Pelegrin, Pablo ^{[4
]}

Bertinaria, Massimo ^{[1
]}

机构：

[1] Univ Turin, Dipartimento Sci & Tecnol Farmaco, Via P Giuria 9, I-10125 Turin, Italy

[2] Univ Pisa, Dept Clin & Expt Med, Via Roma 55, I-56126 Pisa, Italy

[3] Univ Manchester, Fac Biol Med & Hlth, R4-004 AV Hill Bldg,Oxford Rd, Manchester, Lancs, England

[4] Univ Murcia, Univ Clin Hosp Virgen Arrixaca, Biomed Res Inst Murcia IMIBArrixaca, Mol Inflammat Grp, Carretera Buenavista S-N, Murcia 30120, Spain

[5] Natl Inst Chem, Dept Synthet Biol & Immunol, Hajdrihova 19, SI-1000 Ljubljana, Slovenia

[6] Univ Milan, Dipartimento Sci Farmaceut, Via Mangiagalli 25, I-20133 Milan, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 09期

基金：

欧洲研究理事会;

关键词：

MURINE EXPERIMENTAL COLITIS; NF-KAPPA-B; INHIBITION; DESIGN; ACTIVATION; PROTECTS; CELLS; MODEL; MICE; DSS;

D O I：

10.1021/acs.jmedchem.6b01624

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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-1 beta 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.

引用

页码：3656 / 3671

页数：16

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