Discovery of 4-((E)-3,5-dimethoxy-2-((E)-2-nitrovinyl)styryl)aniline derivatives as potent and orally active NLRP3 inflammasome inhibitors for colitis

Xing Xing Zhang; Liang Zhuo Diao; Liu Zeng Chen; Duo Ma; Yu Meng Wang; Han Jiang; Ban Feng Ruan; Xin Hua Liu

doi:10.1016/j.ejmech.2022.114357

Discovery of 4-((E)-3,5-dimethoxy-2-((E)-2-nitrovinyl)styryl)aniline derivatives as potent and orally active NLRP3 inflammasome inhibitors for colitis

Eur J Med Chem. 2022 Jun 5:236:114357. doi: 10.1016/j.ejmech.2022.114357. Epub 2022 Apr 7.

Authors

Xing Xing Zhang¹, Liang Zhuo Diao¹, Liu Zeng Chen², Duo Ma¹, Yu Meng Wang¹, Han Jiang¹, Ban Feng Ruan³, Xin Hua Liu⁴

Affiliations

¹ School of Pharmacy Anhui Medical University, Hefei, 230032, PR China.
² Key Lab of Biofabrication of Anhui Higher Education, Hefei University, Hefei, 230601, PR China.
³ Key Lab of Biofabrication of Anhui Higher Education, Hefei University, Hefei, 230601, PR China. Electronic address: ruanbf@hfuu.edu.cn.
⁴ School of Pharmacy Anhui Medical University, Hefei, 230032, PR China. Electronic address: xhliuhx@163.com.

PMID: 35428012
DOI: 10.1016/j.ejmech.2022.114357

Abstract

NLRP3 inflammasome activation plays a key role in a variety of inflammatory diseases as IBD. Here a series of pterostilbene derivatives were designed and synthesized based on previous SAR, leading to discovery of new effective NLRP3 inflammasome inhibitors with metabolic stability. Among them, the most effective compound 27 showed high inhibitory efficacy (against IL-1 β: IC₅₀ = 1.23 μM) and almost no toxicity (against L02: IC₅₀ > 100 μM). Further mechanism studies have shown that compound 27 directly targets the NLRP3 and affects the assembly of inflammasomes to inhibit the activation of NLRP3 inflammasomes. More importantly, in vitro experiments show that compound 27 has a significant therapeutic effect on DSS-induced colitis in mice with good metabolic stability to liver microsomes (t_1/2 = 138.6 min). This research encourages the further development of more effective NLRP3 inflammasome inhibitors based on this chemical scaffold.

Keywords: IBD; Inhibitor; NLRP3 inflammasome; Pterostilbene derivatives.

MeSH terms

Aniline Compounds / therapeutic use
Animals
Cell Line
Colitis* / chemically induced
Colitis* / drug therapy
Inflammasomes*
Mice
Mice, Inbred C57BL
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism

Substances

Aniline Compounds
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse