Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4-aminopyrrolopyrimidine series of IGF-1R inhibitors

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• 作者：Robin A. Fairhurst^a ; ^{robin.fairhurst@novartis.com" class="auth_mail" title="E-mail the corresponding author} ; Thomas H. Marsilje^b ; Stefan Stutz^a ; Andreas Boos^a ; Michel Niklaus^a ; Bei Chen^b ; Songchun Jiang^b ; Wenshuo Lu^b ; Pascal Furet^a ; Clive McCarthy^a ; Fré ; dé ; ric Stauffer^a ; Vito Guagnano^a ; Andrea Vaupel^a ; Pierre-Yves Michellys^b ; Christian Schnell^a ; Sé ; bastien Jeay^a
• 关键词：Oncology ; Kinase inhibitor ; Insulin-like growth factor receptor-1
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：26
• 期：8
• 页码：2057-2064
• 全文大小：1417 K

文摘

Taking the pyrrolopyrimidine derived IGF-1R inhibitor NVP-AEW541 as the starting point, the benzyl ether back-pocket binding moiety was replaced with a series of 2-cyclic ether methyl ethers leading to the identification of novel achiral [2.2.1]-bicyclic ether methyl ether containing analogues with improved IGF-1R activities and kinase selectivities. Further exploration of the series, including a fluorine scan of the 5-phenyl substituent, and optimisation of the sugar-pocket binding moiety identified compound 33 containing (S)-2-tetrahydrofuran methyl ether 6-fluorophenyl ether back-pocket, and cis-N-Ac-Pip sugar-pocket binding groups. Compound 33 showed improved selectivity and pharmacokinetics compared to NVP-AEW541, and produced comparable in vivo efficacy to linsitinib in inhibiting the growth of an IGF-1R dependent tumour xenograft model in the mouse.