期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 27, 期 8, 页码 1646-1657出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.03.009
关键词
Janus kinase; JAK3 inhibitors; Pyrimidine-4,6-diamine derivatives; Cys909
资金
- National Natural science Foundation of China [81573445, 81172934]
- Beijing Municipal Natural Science Foundation [7182115]
Janus kinases (JAKs) play a key role in the proliferation, apoptosis and differentiation of immune cells, and JAKs are considered as an attractive target for the treatment of inflammatory and autoimmune diseases. Here we show the design and optimization of pyrimidine-4,6-diamine derivatives as selectivity JAK3 inhibitors. Compound 11e, which might interact with unique cysteine (Cys909) residue in JAK3, exhibited excellent JAK3 inhibitory activity (IC50 = 2.1 nM) and high JAK kinase selectivity. In cellular assay, 11e showed moderate potency inhibiting IL-2-stimulated T cell proliferation. The data supports the further development of novel JAKs inhibitors.
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