Structural optimization of diphenylpyrimidine derivatives (DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors with improved activity toward B leukemia cell lines

Eur J Med Chem. 2017 Jan 27:126:444-455. doi: 10.1016/j.ejmech.2016.11.047.

Dan Zhao ¹, Shanshan Huang ¹, Menghua Qu ¹, Changyuan Wang ¹, Zhihao Liu ¹, Zhen Li ¹, Jinyong Peng ¹, Kexin Liu ¹, Yanxia Li ², Xiaodong Ma ³, Xiaohong Shu ⁴

Affiliations

1 College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
2 Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
3 College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaodong.ma@139.com.
4 College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaohong_shu@dmu.edu.cn.

PMID: 27912175 DOI: 10.1016/j.ejmech.2016.11.047

Abstract

A new series of diphenylpyrimidine derivatives (DPPYs) bearing various aniline side chains at the C-2 position of pyrimidine core were synthesized as potent Btk inhibitors. Most of these inhibitors displayed improved activity against B leukemia cell lines compared with lead compound spebrutinib. Subsequent studies showed that the peculiar inhibitor 7j, with IC₅₀ values of 10.5 μM against Ramos cells and 19.1 μM against Raji cells, also displayed slightly higher inhibitory ability than the novel agent ibrutinib. Moreover, compound 7j is not sensitive to normal cells PBMC, indicating low cell cytotoxicity. In addition, flow cytometry analysis indicated that 7j significantly induced the Apoptosis of Ramos cells, and arrested the cell cycle at the G0/G1 phase. These explorations provided new clues to discover pyrimidine scaffold as more effective Btk inhibitors.

Keywords

BTK; Inhibitor; Leukemia; Pyrimidine; Synthesis.

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