设计、合成及喹唑啉衍生物的药理学评价作为新型、强效的泛 JAK 抑制剂。
Design, synthesis, and pharmacological evaluation of quinazoline derivatives as novel and potent pan-JAK inhibitors.
机构信息
The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, PR China.
Central Research Institute, National Key Laboratory of Innovative Immunotherapy, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203, PR China.
出版信息
Bioorg Chem. 2023 Nov;140:106765. doi: 10.1016/j.bioorg.2023.106765. Epub 2023 Aug 7.
Janus kinases (JAKs) play a critical role in modulating the function and expression of inflammatory cytokines related to rheumatoid arthritis (RA). Herein, we report the design, synthesis, and structure-activity relationships (SARs) of a series of novel quinazoline derivatives as JAK inhibitors. Among these inhibitors, compound 11n showed high potency against JAKs (JAK1/JAK2/JAK3/TYK2, IC = 0.40, 0.83, 2.10, 1.95 nM), desirable metabolic characters, and excellent pharmacokinetic properties. In collagen-induced arthritis (CIA) models, compound 11n exhibited significant reduction in joint swelling with good safety, which could be served as a potential therapeutic candidate for the treatment of inflammatory diseases.
Janus 激酶（JAKs）在调节与类风湿关节炎（RA）相关的炎症细胞因子的功能和表达方面发挥着关键作用。在此，我们报告了一系列新型喹唑啉衍生物作为 JAK 抑制剂的设计、合成和构效关系（SAR）。在这些抑制剂中，化合物 11n 对 JAKs（JAK1/JAK2/JAK3/TYK2，IC=0.40、0.83、2.10、1.95nM）具有高活性、良好的代谢特征和优异的药代动力学性质。在胶原诱导性关节炎（CIA）模型中，化合物 11n 表现出显著的关节肿胀减轻作用，且安全性良好，有望成为治疗炎症性疾病的潜在治疗候选药物。
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