Structure-Based Design and Synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino Derivatives as Janus Kinase 3 Inhibitors

Yuan Yin, Cheng-Juan Chen, Ru-Nan Yu, Zhi-Jian Wang, Tian-Tai Zhang, Da-Yong Zhang

Index: 10.1016/j.bmc.2018.04.005

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Abstract

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 compound 12a, which exhibited potent JAK3 inhibitory activity (IC50 of 6.2 nM) as well as excellent JAK kinase selectivity (>60 fold). In cellular assay, 12a exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation (IC50 of 9.4 μM). Further, Compound 12a showed efficacy in delayed hypersensitivity assay. The data supports the further investigation of these compounds as novel JAKs inhibitors.