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

被引：19
|
作者：
Zheng, Nan [1 ,2 ]
Pan, Jing [1 ,2 ]
Hao, Qun [1 ]
Li, Yingxia [2 ]
Zhou, Weicheng [1 ]
机构：
[1] China State Inst Pharmaceut Ind, Shanghai Inst Pharmaceut Ind, State Key Lab New Drug & Pharmaceut Proc, Shanghai Key Lab Antiinfect, 285 Gebaini Rd, Shanghai 201203, Peoples R China
[2] Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2018年 / 26卷 / 08期
关键词：
BTK inhibitors; 3-Substituted pyrazolopyrimidine; Structure-based drug design; Inhibitory activity; ClogP; ANTICANCER DRUG IBRUTINIB; B-CELL; ARTHRITIS; DISCOVERY; RIGIDITY; RECEPTOR;
D O I：
10.1016/j.bmc.2018.03.017
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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 mu M against Ramos cells and 1.80 mu M 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. (C) 2018 Elsevier Ltd. All rights reserved.
引用
收藏
页码：2165 / 2172
页数：8
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