RT Journal Article
T1 Synthesis and pharmacological evaluation of new n‑nulfonylureas as nlrp3 inflammasome inhibitors: identification of a hit compound to treat gout
A1 Narros-Fernández, Paloma
A1 Chioua, Mourad
A1 Petcu, Sonia
A1 Diez-Iriepa, Daniel
A1 Cerrada-Gálvez, Laura
A1 Decouty-Pérez, Céline
A1 Palomino Antolín, Alejandra
A1 Ramos Alonso, Eva
A1 Farré-Alins, Victor
A1 López-Rodríguez, Ana Belén
A1 Romero Martínez, Manuel Alejandro
A1 Marco Contelles, José Luis
A1 Egea, Javier
AB NLRP3 is involved in the pathophysiology of several inflammatory diseases. Therefore, there is high current interest in the clinical development of new NLRP3 inflammasome small inhibitors to treat these diseases. Novel N-sulfonylureas were obtained by the replacement of the hexahydroindacene moiety of the previously described NLRP3 inhibitor MCC950. These new derivatives show moderate to high potency in inhibiting IL-1β release in vitro. The greatest effect was observed for compound 4b, which was similar to MCC950. Moreover, compound 4b was able to reduce caspase-1 activation, oligomerization of ASC, and therefore, IL-1β processing. Additional in silico predictions confirmed the safety profile of compound 4b, and in vitro studies in AML12 hepatic cells confirmed the absence of toxicological effects. Finally, we evaluated in vivo anti-inflammatory properties of compound 4b, which showed a significant anti-inflammatory effect and reduced mechanical hyperalgesia at 3 and 10 mg/kg (i.p.) in an in vivo mouse model of gout.
PB ACS Publications
YR 2022
FD 2022-04-11
LK https://hdl.handle.net/20.500.14352/116946
UL https://hdl.handle.net/20.500.14352/116946
LA eng
NO Paloma Narros-Fernández, Mourad Chioua, Sonia A. Petcu, Daniel Diez-Iriepa, Laura Cerrada-Gálvez, Céline Decouty-Pérez, Alejandra Palomino-Antolín, Eva Ramos, Víctor Farré-Alins, Ana Belén López-Rodríguez, Alejandro Romero, José Marco-Contelles, and Javier Egea. Synthesis and Pharmacological Evaluation of New N-Sulfonylureas as NLRP3 Inflammasome Inhibitors: Identification of a Hit Compound to Treat Gout. Journal of Medicinal Chemistry 2022 65 (8), 6250-6260 DOI: 10.1021/acs.jmedchem.2c00149
NO Author Contributions:P.N.-F., M.C., and S.A.P. contributed equally to this work. Conceptualization: P.N.-F. and J.E.; methodology: P.N.-F., M.C., S.A.P., D.D.-I., L.C-G., and A.R.; validation: P.N.-F. and J.E.; formal analysis: P.N.-F., L.C.-G., and A.B.L.-R.; investigation: P.N.-F., M.C., S.A.P., D.D.-I., C.D.-P., A.P.-A., E.R., V.F.-A., and A.B.L.-R.; resources: J.E. and J.M.-C.; data curation: P.N.-F. and J.E.; writing─original draft preparation: P.N.-F. and J.E.; writing─review and editing: all authors; visualization: P.N.-F. and J.E.; supervision: J.E., A.R., E.R., and J.M.-C.; project administration: J.E.; funding acquisition: J.E., A.R., and J.M.-C. All authors have read and agreed to the published version of the manuscript.
NO Instituto de Salud Carlos III
NO European Commission
DS Docta Complutense
RD 26 ene 2026