A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFR^L858R/T790M mutant with improved pharmacokinetic properties

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• 作者：Lei Yu^a ; ^b ; Minhao Huang^a ; ^b ; Tianfeng Xu^a ; ^b ; Linjiang Tong^d ; Xiao-e Yan^e ; Zhang Zhang^a ; Yong Xu^a ; Caihong Yun^e ; Hua Xie^d ; ^{hxie@simm.ac.cn} ; Ke Ding^a ; ^c ; ^{ding_ke@gibh.ac.cn} ; Xiaoyun Lu^c ; ^{luxy2016@jnu.edu.cn}
• 关键词：EGFRT790M mutant ; Pyrido[2 ; 3-d]pyrimidin-7-ones ; Pharmacokinetic property ; NSCLC ; Irreversible inhibitor
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：27 January 2017
• 年：2017
• 卷：126
• 期：Complete
• 页码：1107-1117
• 全文大小：1331 K
• 卷排序：126

文摘

Optimization of pyrido[2,3-d]pyrimidin-7-ones with improved pharmacokinetic properties. Compound 9s potently suppressed EGFRL858R/T790M kinase and H1975 cells. Compound 9s exhibited moderate plasma exposure and an oral bioavailability value of 16%.