Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 27, Issue 8, Pages 1646-1657Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.03.009
Keywords
Janus kinase; JAK3 inhibitors; Pyrimidine-4,6-diamine derivatives; Cys909
Funding
- National Natural science Foundation of China [81573445, 81172934]
- Beijing Municipal Natural Science Foundation [7182115]
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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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