NLRP3-IN-83 is a selective and orally active inhibitor of NLRP3 inflammasome activation. It effectively inhibits IL-1β activity by blocking NLRP3, with an IC50 of 1.4 μM, independently of NF-κB signaling. NLRP3-IN-83 exhibits a slight inhibitory effect on the AIM2 inflammasome pathway and no effect on the NLRC4 inflammasome. It prevents pyroptosis and demonstrates significant anti-inflammatory effects in a model of ulcerative colitis. NLRP3-IN-83 is applicable for research in inflammatory bowel disease (IBD).

NLRP3-IN-83 (Compound 10) effectively inhibits IL-1β release in LPS-pretreated J774A.1 cells, mouse BMDMs (stimulated with Nigericin or SiO2), and PMA-differentiated human THP-1 macrophages in a concentration-dependent manner at 0.625-5 μM over 1-25 hours. At concentrations of 1-5 μM for 2 hours, it significantly reduces levels of caspase-1 (p20) and IL-1β in the supernatant of LPS-pretreated J774A.1 cells without altering intracellular pro-caspase-1, pro-IL-1β, NLRP3, and ASC expression levels. Additionally, NLRP3-IN-83 at 1-5 μM prevents pyroptosis in these cells by inhibiting GSDMD cleavage and decreasing LDH release. In J774A.1 macrophages and HEK-293T human embryonic kidney cells, 2.5-10 μM of the compound over 24 hours shows no significant toxicity. Furthermore, NLRP3-IN-83 at 1-5 μM for 2-6 hours suppresses activation of the NLRP3 inflammasome without significantly affecting the NF-κB signaling pathway.

NLRP3-IN-83 (Compound 10), administered at 10-20 mg/kg via intragastric route once daily for 7 consecutive days, demonstrated significant anti-inflammatory effects in a DSS-induced ulcerative colitis model.