title: Design, Synthesis, and Evaluation of Acrylamide Derivatives as Direct NLRP3 Inflammasome Inhibitors.
abstract: NLRP3 inflammasome plays a key role in the intracellular activation of caspase-1, processing of pro-inflammatory interleukin-1β (IL-1β), and pyroptotic cell death cascade. The overactivation of NLRP3 is implicated in the pathogenesis of autoinflammatory diseases, known as cryopyrin-associated periodic syndromes (CAPS), and in the progression of several diseases, such as atherosclerosis, type-2 diabetes, gout, and Alzheimer's disease. In this study, the synthesis of acrylamide derivatives and their pharmaco-toxicological evaluation as potential inhibitors of NLRP3-dependent events was undertaken. Five hits were identified and evaluated for their efficiency in inhibiting IL-1β release from different macrophage subtypes, including CAPS mutant macrophages. The most attractive hits were tested for their ability to inhibit NLRP3 ATPase activity on human recombinant NLRP3. This screening allowed the identification of 14, 2-(2-chlorobenzyl)-N-(4-sulfamoylphenethyl)acrylamide, which was able to concentration-dependently inhibit NLRP3 ATPase with an IC50 value of 74 μm. The putative binding pose of 14 in the ATPase domain of NLRP3 was also proposed.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy.
authors.forename: Mattia
authors.identifier: 0000-0003-4358-8599
authors.initials: M
authors.lastname: Cocco
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy.
authors.forename: Gianluca
authors.identifier: 0000-0002-6602-2099
authors.initials: G
authors.lastname: Miglio
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy.
authors.forename: Marta
authors.identifier: 0000-0002-3282-1220
authors.initials: M
authors.lastname: Giorgis
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy.
authors.forename: Davide
authors.identifier: 0000-0002-9455-8317
authors.initials: D
authors.lastname: Garella
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy.
authors.forename: Elisabetta
authors.identifier: 0000-0002-3638-5219
authors.initials: E
authors.lastname: Marini
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy.
authors.forename: Annalisa
authors.identifier: 0000-0002-8590-5196
authors.initials: A
authors.lastname: Costale
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy.
authors.forename: Luca
authors.identifier: 0000-0001-7199-7141
authors.initials: L
authors.lastname: Regazzoni
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy.
authors.forename: Giulio
authors.identifier: 0000-0002-3939-5172
authors.initials: G
authors.lastname: Vistoli
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milano, Italy.
authors.forename: Marica
authors.identifier: 0000-0003-1558-9551
authors.initials: M
authors.lastname: Orioli
authors.affiliation: CIRI, International Center for Infectiology Research, Inserm U1111, CNRS UMR 5308, Ecole Normale Supérieure de Lyon, Université Lyon 1, 21 avenue Tony Garnier, 69007, Lyon, France.
authors.forename: Raïhane
authors.identifier: 0000-0003-0482-8780
authors.initials: R
authors.lastname: Massulaha-Ahmed
authors.affiliation: CIRI, International Center for Infectiology Research, Inserm U1111, CNRS UMR 5308, Ecole Normale Supérieure de Lyon, Université Lyon 1, 21 avenue Tony Garnier, 69007, Lyon, France.
authors.forename: Isabelle
authors.identifier: 0000-0003-0960-3548
authors.initials: I
authors.lastname: Détraz-Durieux
authors.affiliation: CIRI, International Center for Infectiology Research, Inserm U1111, CNRS UMR 5308, Ecole Normale Supérieure de Lyon, Université Lyon 1, 21 avenue Tony Garnier, 69007, Lyon, France.
authors.forename: Marine
authors.identifier: 0000-0003-3258-0268
authors.initials: M
authors.lastname: Groslambert
authors.affiliation: CIRI, International Center for Infectiology Research, Inserm U1111, CNRS UMR 5308, Ecole Normale Supérieure de Lyon, Université Lyon 1, 21 avenue Tony Garnier, 69007, Lyon, France.
authors.forename: Bénédicte F
authors.identifier: 0000-0001-6716-7807
authors.initials: BF
authors.lastname: Py
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125, Torino, Italy. massimo.bertinaria@unito.it.
authors.forename: Massimo
authors.identifier: 0000-0002-2533-5830
authors.initials: M
authors.lastname: Bertinaria
mesh_terms: D020106:Acrylamide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D058847:Inflammasomes / Q000037:antagonists & inhibitors* / Q000235:genetics; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D020106:Acrylamide
keywords: acrylamide derivatives; drug design; inflammasomes; inflammation; pyroptosis