新型BCR-ABL抑制剂的设计合成与构效关系  

Design,synthesis and structure-activity relationship of a series of novel BCRABL inhibitors

作　　者：王永健 郭明 WANG Yongjian;GUO Ming(College of Pharmacy,Nanjing University of Chinese Medicine,Nanjing 210046,China)

机构地区：[1]南京中医药大学药学院,南京210046

出　　处：《中国药科大学学报》2024年第3期357-366,共10页Journal of China Pharmaceutical University

摘　　要：通过对现有的BCR-ABL变构抑制剂阿西米尼(asciminib)进行结构优化研究,得到N-苯基吲哚啉-5-甲酰胺分子骨架Ⅰ,并以该分子骨架为基础,利用分子对接辅助设计合成化合物1~12,使用ESI-MS和NMR对其进行结构表征,后续采用CCK-8法测定目标化合物在体外抗BCR-ABL1依赖型Luc-Ba/F3细胞增殖能力。最终筛选出高活性先导化合物1,针对该化合物在后续成药性评价中暴露出的清除率高、半衰期短等问题进行了其成药性质优化,引入亲水性基团,后续设计并合成化合物13~22,其中化合物17具有较好的细胞抑制活性,清除率较低,半衰期较长,有望作为临床候选化合物展开进一步的生物活性和成药性的评价。In this study,molecular skeleton Ⅰ N-phenylindoline-5-formamide was obtained by optimizing the structure of the existing allosteric BCR-ABL inhibitor asciminib.Based on this molecular skeleton,compounds 1-12 were designed and synthesized assisted by molecular docking.After characterizing their structures using ESIMS and NMR,the anti-BCR-ABL1-dependent Luc-Ba/F3 cell proliferation activity of the target compounds in vitro was determined by CCK-8 assay.Finally,highly active lead compound 1 was screened out.For high clearance rate and short half-life period exposed in subsequent druggability evaluation,its druggability was optimized by introducing hydrophilic groups.Afterwards,compounds 13-22 were designed and synthesized.Compound 17 presented high cell inhibitory activity,low clearance rate and long half-life,and is expected to be used as a clinical candidate for further evaluation of biological activity and druggability.

关 键 词：慢性髓细胞性白血病 BCR-ABL融合蛋白 酪氨酸激酶抑制剂 

分 类 号：R914[医药卫生—药物化学]