Novel 1H-pyrazolo[3,4-d]pyrimidin-6-amino derivatives as potent selective Janus kinase 3 (JAK3) inhibitors. Evaluation of their improved effect for the treatment of rheumatoid arthritis.
Novel 1H-pyrazolo[3,4-d]pyrimidin-6-amino derivatives as potent selective Janus kinase 3 (JAK3) inhibitors. Evaluation of their improved effect for the treatment of rheumatoid arthritis.
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DOI：
10.1016/j.bioorg.2020.103720
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发表时间：
2020-03
影响因子：
5.1
通讯作者：
Yuan Yin;Chengjuan Chen;Ru-Nan Yu;Lei Shu;Zhi-jian Wang;Tian-tai Zhang;Da-yong Zhang
中科院分区：
文献类型：
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作者：
Yuan Yin;Chengjuan Chen;Ru-Nan Yu;Lei Shu;Zhi-jian Wang;Tian-tai Zhang;Da-yong Zhang
选择性JAK3抑制剂已被证明在治疗自身免疫性疾病方面有潜在的好处。在这里，我们报告了一系列吡唑并嘧啶类化合物作为有效的JAK3抑制剂的鉴定，这些化合物利用JAK3中独特的半胱氨酸(Cys909)残基。大多数化合物(13k、13nt和13t)表现出比tofacitinib更强的抗JAK3激酶活性和选择性。此外，最活跃的抑制剂13t(IC50=0.1nM)也对含有相同半胱氨酸的9个激酶中的JAK3显示出良好的选择性。在一系列细胞分裂素估计的细胞分析中，化合物13t可以有效地阻断JAK3-STAT信号通路。进一步的生物学研究，包括细胞抗增殖活性分析和用于体内评估的大鼠佐剂诱导的关节炎模型，也表明它在治疗类风湿关节炎方面的有效性和低毒性。这些实验探索的结果表明，13是一种有希望的先导化合物，可用于开发具有治疗类风湿关节炎潜力的选择性JAK3抑制剂。
Selective JAK3 inhibitors have been shown to have a potential benefit in the treatment of autoimmune disorders. Here we report the identification of a series of pyrazolopyrimidine derivatives as potent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Most of these compounds (13k,13nand13 t), displayed stronger anti-JAK3 kinase activity and selectivity than tofacitinib. Furthermore, the most active inhibitor13t(IC50= 0.1 nM), also exhibited favourable selectivity for JAK3 in a panel of 9 kinases which contain the same cysteine. In a series of cytokinestimulated cellular analysis, compound13 t, could potently block the JAK3-STAT signaling pathway. Further biological studies, including cellular antiproliferative activity assays and a rat adjuvant-induced arthritis model for in vivo evaluation, also indicated its efficacy and low toxicity in the treatment of rheumatoid arthritis. The results of these experimental explorations suggested that13tis a promising lead compound for the development of selective JAK3 inhibitor with therapeutic potential in rheumatoid arthritis.