新型BCR-ABL抑制剂的设计合成与构效关系OA北大核心CSTPCD
Design,synthesis and structure-activity relationship of a series of novel BCR-ABL inhibitors
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 ESI-MS 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.
王永健;郭明
南京中医药大学药学院,南京 210046
药学
慢性髓细胞性白血病BCR-ABL融合蛋白酪氨酸激酶抑制剂
chronic myeloid leukemiaBCR-ABL fusion proteintyrosine kinase inhibitors
《中国药科大学学报》 2024 (003)
357-366 / 10
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