Design, synthesis and biological study of BTK/JAK3 dual-target inhibitors

VernacularTitle:BTK/JAK3双靶点抑制剂的设计合成和生物活性评价
Author: Lifang CEN ; Ming CHENG ; Weijie REN ; Liu YE ; Luhua WANG ; Weibo GUO ; Qiang ZHANG ; Yungen XU
Publication Type:Journal Article
Keywords: rheumatoid arthritis / BTK inhibitor / JAK3 inhibitor / dual-target inhibitors / anti-inflammatory
From: Journal of China Pharmaceutical University 2024;55(1):73-86
CountryChina
Language:Chinese
Abstract: Abstract: In the present study, the compound XL-12 from our previous work was utilized as a lead compound. Through the optimization of the terminal phenyl ring, 12 target compounds were designed and synthesized. The structures of all target compounds were confirmed by 1H NMR, 13C NMR, and H RMS. In vitro enzyme activity assay showed that most compounds demonstrated significant inhibitory activity toward Bruton’s tyrosine kinase (BTK) and Janus kinase 3 (JAK3). Among them, compound I-3 exhibited moderate cell proliferation inhibitory activity toward Daudi cells and BaF3-JAK3 cells. In the evaluation of anti-inflammatory activity in vitro, compound I-3 could effectively inhibit the production of inflammatory factors IL-6; besides, it exhibited superior anti-inflammatory activity compared to ibrutinib in xylene-induced ear swelling model in mice.