Synthesis and pharmacological validation of fluorescent diarylsulfonylurea analogues as NLRP3 inhibitors and imaging probes

Eur J Med Chem. 2022 Apr 4;237:114338. doi: 10.1016/j.ejmech.2022.114338. Online ahead of print.ABSTRACTThe NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) is a key cytosolic pattern recognition receptor that senses diverse pathogen- and host-originated threat signals. Aberrant activation of NLRP3 inflammasomes is closely associated with the pathogenesis of various complex inflammatory diseases. Nevertheless, the detailed regulation mechanism of NLRP3 inflammasome and its pathogenic roles in the inflammation progression remain to be fully elucidated. Fluorescent imaging with small molecule probe can provide valuable visualization information on the expression, occupancy and bio-distribution of target protein. Herein, we reported a series of diarylsulfonylurea NLRP3 fluorescent inhibitors bearing an amino benzodiazole fluorophore. Compared to the previously reported NLRP3 fluorescent probes, these inhibitors are more structurally concise and membrane permeable due to no additionally appended fluorophore via a linker. Among this series, compound 13a exhibited the most potent cellular NLRP3 inhibitory effect with an IC50 value of 49 nM, and significantly suppressed LPS/Nigericin-induced secretion of active caspase-1 and mature IL-1β in a dose-dependent manner to block the activation of NLRP3 inflammasome. Meanwhile, this new probe exhibited promising fluorescent properties for specifically detecting and imaging the LPS-induced or constitutively expressed NLRP...

Source: European Journal of Medicinal Chemistry - April 18, 2022 Category: Chemistry Authors: Jiannan Zhao Yongling Li Jing Ma Jingting Liu Ruoxuan Xiao Linlin Wang Peng Li Yinyan He Feng Qian Ao Zhang Zhen-Liang Sun Chunyong Ding Source Type: research