posted on 2022-03-07, 17:04authored byRuijia Zhang, Feng Hong, Min Zhao, Xiaoying Cai, Xueqin Jiang, Neng Ye, Kaiyue Su, Na Li, Minghai Tang, Xu Ma, Hengfan Ni, Lun Wang, Li Wan, Lijuan Chen, Wenshuang Wu, Haoyu Ye
The NLRP3 inflammasome has now emerged
as one of the most appealing
drug targets for many inflammation-related diseases. Velutone F, a
natural NLPR3 inhibitor, identified in our previous study has been
limited in application by its low in planta abundance, weak activity,
and complicated synthetic routes. To address these needs, structural
optimization of velutone F led to a series of novel NLRP3 inhibitors.
Among them, compound 14c exerted remarkable inhibitory
activity with an IC50 value in the nanomolar range (251.1
nM) and was approximately 5-fold more potent than velutone F. Moreover,
the synthesis method of 14c was simple, easy to handle,
and scalable. Compound 14c could suppress NLRP3 inflammasome
activation by attenuating ASC speck formation. Most importantly, compound 14c reduced peritoneal neutrophil influx in mice and IL-1β
in the spleen in the MSU-induced peritonitis in LPS-primed mouse model.
Taken together, compound 14c is a prospective lead compound
in the discovery of NLRP3 inflammasome inhibitors.