The NLRP3 inflammasome is an important regulator of the sterile inflammatory response, and its activation by host-derived sterile molecules leads to the intracellular activation of caspase-1, processing of the pro-inflammatory cytokines interleukin-1β (IL-1β)/IL-18, and pyroptotic cell death. Inappropriate activation of NLRP3 drives a chronic inflammatory response and is implicated in several non-communicable diseases, including gout, atherosclerosis, type II diabetes and Alzheimer's disease. In this study, we report the design, synthesis and biological evaluation of novel boron compounds (NBCs) as NLRP3 inflammasome inhibitors. Structure-activity relationships (SAR) show that 4-fluoro substituents on the phenyl rings retain NLRP3 inhibitory activity, whereas more steric and lipophilic substituents diminish activity. Loss of inhibitory activity is also observed if the CCl3 group on the oxazaborine ring is replaced by a CF3 group. These findings provide additional understanding of the NBC series and will aid in the development of these NLRP3 inhibitors as tool compounds or therapeutic candidates for sterile inflammatory diseases.

中文翻译：

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NLRP3 炎症小体奥沙硼啉抑制剂的设计、合成和评估。

NLRP3炎症小体是无菌炎症反应的重要调节因子，其被宿主衍生的无菌分子激活导致胞内caspase-1的激活，促炎细胞因子白细胞介素-1β（IL-1β）/IL-的处理。 18、焦亡细胞死亡。NLRP3 的不当激活会引发慢性炎症反应，并与多种非传染性疾病有关，包括痛风、动脉粥样硬化、II 型糖尿病和阿尔茨海默病。在这项研究中，我们报告了作为 NLRP3 炎性体抑制剂的新型硼化合物 (NBC) 的设计、合成和生物学评价。结构-活性关系 (SAR) 显示苯环上的 4-氟取代基保留了 NLRP3 抑制活性，而更多的空间和亲脂性取代基会降低活性。如果恶唑硼啉环上的 CCl3 基团被 CF3 基团取代，也会观察到抑制活性的丧失。这些发现提供了对 NBC 系列的更多了解，并将有助于开发这些 NLRP3 抑制剂作为无菌炎症性疾病的工具化合物或治疗候选药物。