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

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

doi:10.1016/j.bmc.2019.03.009

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. Epub 2019 Mar 5.

Authors

Ru-Nan Yu¹, Cheng-Juan Chen², Lei Shu¹, Yuan Yin¹, Zhi-Jian Wang¹, Tian-Tai Zhang³, Da-Yong Zhang⁴

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: [email protected].
⁴ College of Science, China Pharmaceutical University, Nanjing, PR China. Electronic address: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Cell Proliferation / drug effects
Diamines / chemistry*
Diamines / metabolism
Diamines / pharmacology
Drug Design*
Humans
Janus Kinase 1 / antagonists & inhibitors
Janus Kinase 1 / metabolism
Janus Kinase 2 / antagonists & inhibitors
Janus Kinase 2 / metabolism
Janus Kinase 3 / antagonists & inhibitors*
Janus Kinase 3 / metabolism
Molecular Docking Simulation
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Structure, Tertiary
Pyrimidines / chemistry*
Pyrimidines / metabolism
Pyrimidines / pharmacology
Rats
Structure-Activity Relationship
T-Lymphocytes / cytology
T-Lymphocytes / drug effects
T-Lymphocytes / metabolism

Substances

Diamines
Protein Kinase Inhibitors
Pyrimidines
pyrimidine-4,6-diamine
Janus Kinase 1
Janus Kinase 2
Janus Kinase 3