Structure-based design and synthesis of pyrimidine-4,6-diamine derivatives as Janus kinase 3 inhibitors

Bioorg Med Chem. 2019 Apr 15;27(8):1646-1657. doi: 10.1016/j.bmc.2019.03.009.

Ru-Nan Yu ¹, Cheng-Juan Chen ², Lei Shu ¹, Yuan Yin ¹, Zhi-Jian Wang ¹, Tian-Tai Zhang ³, Da-Yong Zhang ⁴

Affiliations

1 College of Science, China Pharmaceutical University, Nanjing, PR China.
2 Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
3 Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China. Electronic address: ttzhang@imm.ac.cn.
4 College of Science, China Pharmaceutical University, Nanjing, PR China. Electronic address: cpuzdy@163.com.

PMID: 30853331 DOI: 10.1016/j.bmc.2019.03.009

Abstract

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.

Keywords

Cys909; JAK3 inhibitors; Janus kinase; Pyrimidine-4,6-diamine derivatives.

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