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新型构象受限茚满类似物作为突变型异柠檬酸脱氢酶1（IDH1）抑制剂的发现及构效关系研究

Discovery and structure-activity-relationship study of novel conformationally restricted indane analogues for mutant isocitric dehydrogenase 1 (IDH1) inhibitors.

作者信息

Zheng Qiangang, Tang Shuai, Fu Xianlei, Chen Ziqi, Ye Yan, Lan Xiaojing, Jiang Lei, Huang Ying, Ding Jian, Geng Meiyu, Huang Min, Wan Huixin

机构信息

Shanghai Haihe Pharmaceutical, Co., Ltd., 421 Newton Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China.

Shanghai Institute of Materia Medica, Chinese Academy of Science, 555 Zuchongzhi Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China.

出版信息

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5262-5266. doi: 10.1016/j.bmcl.2017.10.029. Epub 2017 Oct 16.

DOI:10.1016/j.bmcl.2017.10.029
PMID:29079473
Abstract

The discovery and optimization of various of indane amides as mutant IDH1 inhibitors via structure-based rational design were reported. The optimal compounds demonstrated both potent inhibition in IDH1 enzymatic activity and 2HG production in IDH1 mutant HT1080 cell line, favorable PK properties and great selectivity against IDH1 and IDH2.

摘要

通过基于结构的合理设计发现并优化了多种茚满酰胺作为突变型异柠檬酸脱氢酶1（IDH1）抑制剂。这些优化后的化合物在IDH1酶活性和IDH1突变体HT1080细胞系中2-羟基戊二酸（2HG）生成方面均表现出强效抑制作用，具有良好的药代动力学（PK）性质，并且对IDH1和IDH2具有高度选择性。

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