Anilinoquinazoline inhibitors of the RET kinase domain—Elaboration of the 7-position

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• 作者：Allan M. Jordan^a ; ; Habiba Begum^a ; Emma Fairweather^a ; Samantha Fritzl^a ; Kristin Goldberg^a ; Gemma V. Hopkins^a ; Niall M. Hamilton^a ; Amanda J. Lyons^a ; H. Nikki March^a ; Rebecca Newton^a ; Helen F. Small^a ; Swamy Vishwanath^b ; Ian D. Waddell^a ; Bohdan Waszkowycz^a ; Amanda J. Watson^a ; Donald J. Ogilvie^a
• 关键词：Kinase inhibitor ; RET receptor ; Hepatocyte stability ; Targeted therapy ; Lung cancer
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 June 2016
• 年：2016
• 卷：26
• 期：11
• 页码：2724-2729
• 全文大小：1291 K

文摘

We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modification of their physicochemical properties, delivering improvements in cell potency. However, whilst cellular selectivity against key targets could be maintained, combining cell potency and acceptable pharmacokinetics proved challenging.