Synthesis and Pharmacological Evaluation of New N-Sulfonylureasas NLRP3 Inflammasome Inhibitors: Identification of a HitCompound to Treat Gout

NLRP3 is involved in the pathophysiology ofseveral inflammatory diseases. Therefore, there is high currentinterest in the clinical development of new NLRP3 inflammasomesmall inhibitors to treat these diseases. NovelN-sulfonylureas wereobtained by the replacement of the hexahydroindacene moiety ofthe previously described NLRP3 inhibitor MCC950. These newderivatives show moderate to high potency in inhibiting IL-1 beta release in vitro. The greatest effect was observed for compound4b,which was similar to MCC950. Moreover, compound4bwas ableto reduce caspase-1 activation, oligomerization of ASC, andtherefore, IL-1 beta processing. Additional in silico predictionsconfirmed the safety profile of compound4b, and in vitro studiesin AML12 hepatic cells confirmed the absence of toxicologicaleffects. Finally, we evaluated in vivo anti-inflammatory properties of compound4b, which showed a significant anti-inflammatoryeffect and reduced mechanical hyperalgesia at 3 and 10 mg/kg (i.p.) in an in vivo mouse model of gout.

Automated summary

NLRP3 plays a role in various inflammatory diseases, making the development of NLRP3 inflammasome small inhibitors a current area of interest. New N-sulfonylureas were obtained by modifying a previously described NLRP3 inhibitor, MCC950, and these derivatives showed potent inhibitory effects on IL-1 beta release. Compound 4b exhibited the greatest effect, similar to MCC950, and also showed a reduction in caspase-1 activation and IL-1 beta processing. In silico predictions confirmed the safety profile of compound 4b, and in vitro and in vivo studies further supported its anti-inflammatory properties.