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
  • 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: [email protected].
  • 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: [email protected].
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.