Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

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• 作者：Qingbei Zeng ; Jiabing Wang ; Ziqiang Cheng ; Kan Chen ; Peter Johnstr枚m ; Katarina Varn盲s ; David Yunzhi Li ; Zhen Fan Yang ; Xiaolin Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 22, 2015
• 年：2015
• 卷：58
• 期：20
• 页码：8200-8215
• 全文大小：652K
• ISSN：1520-4804

文摘

Recent reports suggest that an increasing number of patients with lung cancer, especially those with activating mutations of the epidermal growth factor receptor (EGFR), also present with brain metastases and leptomeningeal metastases. These patients have poor prognosis as there are no approved drugs for these indications. Available agents have poor efficacy for these patients even at well above their standard dose. Herein, we report the discovery of (4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (2R)-2,4-dimethylpiperazine-1-carboxylate 1m (AZD3759), an investigational drug currently in Phase 1 clinical trial, which has excellent central nervous system penetration and which induces profound regression of brain metastases in a mouse model.