Novel Macrocyclic NLRP3 Inhibitors

Aberrant activation of NLRP3 due to persistent tissue damage, misfolded proteins or crystal deposits has been linked to multiple chronic inflammatory disorders such as cryopyrin-associated periodic syndrome (CAPS), neurodegenerative diseases, gouty arthritis, and numerous others. Hence, there has been an increasing interest in NLRP3 inhibitors as therapeutics. A first generation of NLRP3 inhibitors bearing a sulfonylurea core such as MCC950 (developed by Pfizer) were discovered by phenotypic screening, however their mode of action was only elucidated later. Based on MCC950, second-generation inhibitors were developed, aiming to overcome some liabilities such as moderate potency and drug induced liver injury. During the optimization of these (second-generation) inhibitors, conformational studies led to the design of novel macrocycles. Here we report the discovery and optimization of this class of NLRP3 inhibitors.由于持续性组织损伤、错误折叠蛋白或晶体沉积引发的NLRP3（NLR家族pyrin结构域包含蛋白3）异常激活，与多种慢性炎症性疾病密切相关，例如冷吡啉相关周期性综合征（CAPS）、神经退行性疾病、痛风性关节炎等诸多病症。因此，将NLRP3抑制剂作为治疗药物的研究关注度与日俱增。第一代以磺酰脲为母核的NLRP3抑制剂（如辉瑞（Pfizer）研发的MCC950）通过表型筛选被发现，但其作用机制直至后续才得以阐明。基于MCC950，研究人员开发了第二代NLRP3抑制剂，旨在克服初代药物的部分缺陷，如中等活性及药物性肝损伤。在这类第二代抑制剂的优化过程中，构象研究助力新型大环化合物的设计。本文报道了此类NLRP3抑制剂的发现与优化历程。