Structure-Based Design and Synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino Derivatives as Janus Kinase 3 Inhibitors
Structure-Based Design and Synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino Derivatives as Janus Kinase 3 Inhibitors
复制标题
基于结构的 Janus 激酶 3 抑制剂 1H-吡唑并[3,4-d]嘧啶-4-氨基衍生物的设计与合成
DOI：
10.1016/j.bmc.2018.04.005
复制
发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Zhang dayong
中科院分区：
文献类型：
--
作者：
Yin yuan;Chen chengjuan;Yu runan;Wang zhijian;Zhang tiantai;Zhang dayong
Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. Here we report the discovery and optimization of 1H-pyrazolo[3,4-d]pyrimidin-4-amino as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Our optimization study gave compound12a, which exhibited potent JAK3 inhibitory activity (IC50of 6.2 nM) as well as excellent JAK kinase selectivity (>60-fold). In cellular assay,12aexhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation (IC50of 9.4 μM). Further, compound12ashowed efficacy in delayed hypersensitivity assay. The data supports the further investigation of these compounds as novel JAKs inhibitors.
