Synthesis and pharmacological evaluation of new n‑nulfonylureas as nlrp3 inflammasome inhibitors: identification of a hit compound to treat gout
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2022
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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
Abstract
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.
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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.