Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors

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• 作者：Fré ; dé ; ric Stauffer ; ^{frederic.stauffer@novartis.com" class="auth_mail" title="E-mail the corresponding author} ; Sandra W. Cowan-Jacob ; Clemens Scheufler ; Pascal Furet
• 关键词：IGF-1R inhibitor ; IGF-1R X-ray co-crystal structure ; Structure-guided design
• 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：2065-2067
• 全文大小：688 K

文摘

We report structure-guided modifications of the benzyloxy substituent of the Insulin-like Growth Factor-1 Receptor (IGF-1R) inhibitor NVP-AEW541. This chemical group has been shown to confer selectivity against other protein kinases but at the expense of a metabolism liability. X-ray crystallography has revealed that the benzyloxy moiety interacts with a lysine cation of the IGF-1R kinase domain via its ether function and its aromatic π-system and is nicely embedded in an induced hydrophobic pocket. We show that 1,4-diethers displaying an adequate hydrophobic and constrained shape are advantageous benzyloxy replacements. A single digit nanomolar inhibitor (compound 20, IC₅₀ = 8.9 nM) was identified following this approach.