Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors

被引：29

作者：

Zhang, Long ^{[1
]}

Yang, Yingying ^{[1
]}

Zhou, Haojie ^{[1
]}

Zheng, Qingmei ^{[1
]}

Li, Yuhao ^{[1
]}

Zheng, Shansong ^{[1
]}

Zhao, Shuyong ^{[1
]}

Chen, Dong ^{[1
]}

Fan, Chuanwen ^{[1
]}

机构：

[1] Qilu Pharmaceut Co Ltd, Shandong Prov Key Lab Small Mol Targeted Drugs, Jinan 250100, Shandong, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 102卷

关键词：

Quinazoline derivatives; H1975; EGFR-T790M; HCC827; A-431; GROWTH-FACTOR-RECEPTOR; CELL LUNG-CANCER; TYROSINE KINASE INHIBITORS; IRREVERSIBLE INHIBITORS; EGFR INHIBITOR; ACQUIRED-RESISTANCE; T790M MUTATION; PHASE-II; GEFITINIB; 4-(PHENYLAMINO)QUINAZOLINE;

D O I：

10.1016/j.ejmech.2015.08.026

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies. (C) 2015 Elsevier Masson SAS. All rights reserved.

引用

页码：445 / 463

页数：19

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