Development of novel oridonin analogs as specifically targeted NLRP3 inflammasome inhibitors for the treatment of dextran sulfate sodium-induced colitis

Abnormal activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is closely associated with a variety of inflammatory diseases. Herein, we describe the discovery and optimization of a series of NLRP3 inflammasome inhibitors based on the oridonin skeleton. These inhibitors exhibited moderate to potent inhibitory activity against interleukin 1β (IL-1β) release. Compound E6 showed the strongest inhibitory activity and better safety range against IL-1β (IC50 = 0.45 ± 0.02 μM, selectivity index = 36.49). Compared with oridonin, the activity and selectivity index of compound E6 increased 11.5 and 7.2 times, respectively. Compound E6 also exhibited broad-spectrum activity and specificity. Compound E6 mainly reduced the release of IL-1β by targeting the NLRP3 protein, thereby inhibiting the NLRP3-caspase 1-gasdermin D (GSDMD), as well as inhibiting the caspase 4-GSDMD signaling pathway. Further studies revealed an important therapeutic effect of E6 on dextran sulfate sodium-induced colitis. Compound E6 may be promising for the treatment of NLRP3-related diseases including inflammatory bowel disease. Further studies revealed an important therapeutic effect of E6 on dextran sulfate sodium-induced colitis, with acceptable drug-likeness in vivo and in vitro. [Display omitted] •A series of oridonin analogs containing carbamate as novel NLRP3 inflammasome inhibitors were designed and synthesized.•Compared with oridonin, the inhibitory activity and selectivity index of compound E6 increased 11.5 and 7.2 times, respectively.•Compound E6 could exert a significant therapeutic effect on DSS-induced colitis in vivo.