新型 3-取代吡唑并嘧啶衍生物的设计、合成及作为强效布鲁顿酪氨酸激酶（BTK）抑制剂的生物评价。
Design, synthesis and biological evaluation of novel 3-substituted pyrazolopyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors.
机构信息
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.
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.
出版信息
Bioorg Med Chem. 2018 May 1;26(8):2165-2172. doi: 10.1016/j.bmc.2018.03.017. Epub 2018 Mar 12.
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 (IC = 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.
一系列 3-取代吡唑并嘧啶衍生物作为 BTK 抑制剂，通过基于结构的药物设计进行设计，并通过基于酶的测定法进行合成和评估，以及对 Ramos 和 Raji 细胞的抗增殖作用进行评估。它们大多数对 BTK 和 B 细胞淋巴母细胞白血病系均具有良好的体外抑制活性。其中，化合物 8a 表现出优异的效力（对 BTK 酶的 IC = 7.95 nM，对 Ramos 细胞的 8.91 μM，对 Raji 细胞的 1.80 μM），具有更好的亲水性（ClogP = 3.33）。这些探索为发现 3-取代吡唑并嘧啶衍生物作为新型抗肿瘤药物提供了新的线索。
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