2. Academic Validation
  3. Design, synthesis and biological evaluation of novel 3-substituted pyrazolopyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors

Design, synthesis and biological evaluation of novel 3-substituted pyrazolopyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors

  • Bioorg Med Chem. 2018 May 1;26(8):2165-2172. doi: 10.1016/j.bmc.2018.03.017.
Nan Zheng 1,  Jing Pan 1,  Qun Hao 2,  Yingxia Li 3,  Weicheng Zhou 4
Affiliations

Affiliations

  • 1 Shanghai Key Lab. of Anti-infectives, State Key Lab. of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
  • 2 Shanghai Key Lab. of Anti-infectives, State Key Lab. of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China.
  • 3 School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China. Electronic address: liyx417@fudan.edu.cn.
  • 4 Shanghai Key Lab. of Anti-infectives, State Key Lab. of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China. Electronic address: zhouweicheng58@163.com.
PMID: 29567295 DOI: 10.1016/j.bmc.2018.03.017
Abstract

A series of 3-substituted pyrazolopyrimidine derivatives as Btk inhibitors were designed by structure-based drug design and they were synthesized, evaluated by enzyme-based assay and anti-proliferation against Ramos and Raji cells. Most of them displayed good inhibitory activities against both Btk and B-cell lymphoblastic leukemia lines in vitro. Among them, compound 8a exhibited excellent potency (IC50 = 7.95 nM against BTK Enzyme, 8.91 μM against Ramos cells and 1.80 μM against Raji cells), with a better hydrophilicity (ClogP = 3.33). These explorations provided new clues to discover 3-substituted pyrazolopyrimidine derivatives as novel anti-tumor agents.

Keywords

3-Substituted pyrazolopyrimidine; BTK inhibitors; ClogP; Inhibitory activity; Structure-based drug design.

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