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

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.

Agents for the Treatment of Gout: Current Advances and Future Perspectives

“…Moreover, compound 52a showed a favorable in vitro safety profile, and substantially reduced inflammation and mechanical hyperalgesia in an in vivo mouse model of gout. 113 At present, the development of NLRP3 inhibitors, including MCC950 analogs and several other chemical types, has achieved considerable progress. Several NLRP3 inhibitors have shown good preventive or therapeutic effects on animal models of NLRP3-related diseases, and their application in gout therapy is worthy of future investigation.…”

“…Surprisingly, the activity of compound 52a was equivalent to that of MCC950. Moreover, compound 52a showed a favorable in vitro safety profile, and substantially reduced inflammation and mechanical hyperalgesia in an in vivo mouse model of gout . At present, the development of NLRP3 inhibitors, including MCC950 analogs and several other chemical types, has achieved considerable progress.…”

Role of NLRP3 Inflammasome in Stroke Pathobiology: Current Therapeutic Avenues and Future Perspective

“…An MCC950 structural similar compound 4b exhibited significant anti-inflammatory properties in an animal model of inflammation, possibly by reducing ASC oligomerization, caspase-1 activation, and subsequent IL-1β release. 195 However, the neuroprotective potential of these molecules is yet to be established in experimental stroke models. CY-09, glitazone, has been shown to selectively inhibit NLRP3 oligomerization and inflammasome assembly without any effects on AIM2 nor NLRC4 inflammasome.…”

“…These compounds showed moderate to high inhibitory potential for IL-1β release. An MCC950 structural similar compound 4b exhibited significant anti-inflammatory properties in an animal model of inflammation, possibly by reducing ASC oligomerization, caspase-1 activation, and subsequent IL-1β release . However, the neuroprotective potential of these molecules is yet to be established in experimental stroke models.…”

Novel Aryl Sulfonamide Derivatives as NLRP3 Inflammasome Inhibitors for the Potential Treatment of Cancer

“…These findings prompted the development of potent and selective NLRP3 inhibitors that are extensively used as pharmacological tools to elucidate possible clinical applications of NLRP3 targeting strategies. , In this rapidly expanding research field, numerous compounds are already under preclinical investigation, and few of them have reached phase I/II clinical trials. − Among these, MCC950 ( 1 , Figure ) is the most studied NLRP3 inhibitor after its early discovery in 2003 . MCC950 was shown to block canonical and noncanonical NLRP3 activation at nanomolar concentrations in vitro with high selectivity over AIM2, NLRC4, or NLRP1 inflammasomes .…”