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基于结构导向的吡啶并[2,3-d]嘧啶-7-酮类化合物优化，作为具有改善药代动力学性质的表皮生长因子受体（EGFR）突变体的选择性抑制剂。

A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFR mutant with improved pharmacokinetic properties.

作者信息

Yu Lei, Huang Minhao, Xu Tianfeng, Tong Linjiang, Yan Xiao-E, Zhang Zhang, Xu Yong, Yun Caihong, Xie Hua, Ding Ke, Lu Xiaoyun

机构信息

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu-Chong-Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.

出版信息

Eur J Med Chem. 2017 Jan 27;126:1107-1117. doi: 10.1016/j.ejmech.2016.12.006. Epub 2016 Dec 3.

DOI:10.1016/j.ejmech.2016.12.006
PMID:28033579
Abstract

Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFR inhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFR kinase and inhibited the proliferation of H1975 cells with IC values of 2.0 nM and 40 nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERK in NCIH1975 cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.

摘要

对吡啶并[2,3 - d]嘧啶 - 7 - 酮进行结构优化，以获得一系列具有改善药代动力学性质的新型选择性表皮生长因子受体（EGFR）抑制剂。其中最有前景的化合物9能有效抑制EGFR激酶，并分别以2.0 nM和40 nM的IC值抑制H1975细胞的增殖。该化合物在NCIH1975细胞中剂量依赖性地诱导EGFR磷酸化的降低和细胞外信号调节激酶（ERK）的下游激活。口服给药后，它还表现出适度的血浆暴露，口服生物利用度值为16%。化合物9可能是进一步药物研发中克服非小细胞肺癌（NSCLC）患者获得性耐药的有前景的先导化合物。

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