Discovery of DFV890, a Potent Sulfonimidamide-Containing NLRP3 Inflammasome Inhibitor

The discovery of DFV890 ((R)-1), a potent and selective NLRP3 antagonist, is described. Replacement of the sulfonyl urea core from the first-generation NLRP3 antagonist CRID3 with a sulfonimidamide core afforded a novel and potent series of NLRP3 antagonists. The (R)-enantiomers of the sulfonimidamide series were found to be consistently more potent than structurally related sulfonyl ureas. Replacement of the furan unit of CRID3 with a 5-substituted thiazole unit led to DFV890 ((R)-1), which potently inhibited IL-1β production in THP-1 cells and in primary human cells, blocked multiple downstream effectors of NLRP3 activation, and substantially improved PK properties and significantly lowered the predicted human dose compared to that for CRID3. DFV890 ((R)-1) was also effective in an air pouch model of gout.

本研究报道了强效选择性NLRP3拮抗剂DFV890（(R)-1）的发现历程。将第一代NLRP3拮抗剂CRID3的磺酰脲（sulfonyl urea）母核替换为磺酰亚胺酰胺（sulfonimidamide）母核，得到了一系列新型强效的NLRP3拮抗剂。研究发现，该磺酰亚胺酰胺系列化合物的(R)-对映体活性始终优于结构相关的磺酰脲类化合物。将CRID3的呋喃（furan）单元替换为5-取代噻唑（thiazole）单元，即得到DFV890（(R)-1）；该化合物可强效抑制THP-1细胞及原代人细胞中白细胞介素-1β（IL-1β）的生成，阻断NLRP3激活后的多种下游效应因子，同时显著优化了药代动力学（PK）特性，且相较于CRID3大幅降低了预测的人体给药剂量。DFV890（(R)-1）在痛风气囊模型中同样展现出显著治疗活性。