氮杂吲哚类Janus激酶抑制剂的合成及体外活性评价

Synthesis and in vitro Activity Evaluation of Azo-indole JAK Inhibitors

目的设计并合成用于治疗类风湿性关节炎的Janus激酶抑制剂,进行初步的体外激酶活性评价。方法选择Baricitinib为先导化合物进行结构优化改造,设计合成系列结构全新的小分子化合物,经~1 H-NMR和ESI-MS鉴定目标物结构,并使用毛细管电泳方法通过检测底物肽段磷酸化转化率来进行化合物激酶活性评价。结果合成7个目标化合物,均表现出一定程度的激酶选择性,其中7a和7d的选择性较为突出。结论芳基磺酰胺类化合物因能与JAK1结构中特有的氨基酸间产生π-π共轭而表现出较好的JAK1抑制选择性,值得进一步研究。

Objective To design and synthesize JAK inhibitors for the treatment of rheumatoid arthri- tis and to evaluate the in vitro kinase activity. Methods Baricitinib was selected as the lead compound to op- timize the structure. A novel small molecular compound was designed and synthesized. The structure of the target was identified by 1 H-NMR and ESI-MS.The activity of the compound kinase was evaluated using capillary electrophoresis.Results Seven target compounds were synthesized,which showed some kinase se- lectivity, among which 7a and 7 d were more active.Conclusion Aromatic sulfonamide compounds exhibit better JAK1 inhibition selectivity that is obtained via good π-π interactions between the substituent and histidine present in the glycine-rich loop of JAK1, which merits further study.