Design, Synthesis, and Biological Evaluation of 2-Oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl Derivatives as New Irreversible Epidermal Growth Factor Receptor Inhibitors with Improved Pharmacokin

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• 作者：Shilin Xu ; Tianfeng Xu ; Lianwen Zhang ; Zhang Zhang ; Jinfeng Luo ; Yingxue Liu ; Xiaoyun Lu ; Zhengchao Tu ; Xiaomei Ren ; Ke Ding
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8803-8813
• 全文大小：426K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

Structural optimization of a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl compounds, potential new irreversible EGFR inhibitors, was performed to improve pharmacokinetic properties of the compounds. This led to compound 2v with improved aqueous solubility and good pharmacokinetic properties which at the nanomolar level potently inhibits gefitinib-resistant EGFR^L858R/T790M kinase and displays strong antiproliferative activity against H1975 nonsmall cell lung cancer cells. The new inhibitor also shows promising antitumor efficacy in a murine EGFR^L858R/T790M-driven H1975 xenograft model without effect on body weight. These studies provide new lead compounds for further development of drugs for treatment of gefitinib-resistant nonsmall cell lung cancer patients.