2. Academic Validation
  3. Synthesis and Pharmacological Evaluation of New N-Sulfonylureas as NLRP3 Inflammasome Inhibitors: Identification of a Hit Compound to Treat Gout

Synthesis and Pharmacological Evaluation of New N-Sulfonylureas as NLRP3 Inflammasome Inhibitors: Identification of a Hit Compound to Treat Gout

  • J Med Chem. 2022 Apr 28;65(8):6250-6260. doi: 10.1021/acs.jmedchem.2c00149.
Paloma Narros-Fernández 1 2 3,  Mourad Chioua 4,  Sonia A Petcu 4,  Daniel Diez-Iriepa 4 5,  Laura Cerrada-Gálvez 1 2 3,  Céline Decouty-Pérez 1 2 3,  Alejandra Palomino-Antolín 1 2 3,  Eva Ramos 6,  Víctor Farré-Alins 1 2 3,  Ana Belén López-Rodríguez 1 2 3,  Alejandro Romero 6,  José Marco-Contelles 4,  Javier Egea 1 2 3
Affiliations

Affiliations

  • 1 Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Calle Maestro Vives 2, 28009 Madrid, Spain.
  • 2 IIS-Hospital Universitario de La Princesa, 28006 Madrid, Spain.
  • 3 Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, UAM, Madrid 28029, Spain.
  • 4 Laboratory of Medicinal Chemistry (IQOG, CSIC), Juan de La Cierva 3, Madrid 28006, Spain.
  • 5 Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Ctra. Madrid-Barcelona km 33.6, Alcalá de Henares 28871, Spain.
  • 6 Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid 28040, Spain.
PMID: 35403430 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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