Pharmacophoric Modifications Lead to Superpotent 伪v尾3 Integrin Ligands with Suppressed 伪5尾1 Activity

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• 作者：Stefanie Neubauer ; Florian Rechenmacher ; Richard Brimioulle ; Francesco Saverio Di Leva ; Alexander Bochen ; Tariq R. Sobahi ; Margret Schottelius ; Ettore Novellino ; Carlos Mas-Moruno ; Luciana Marinelli ; Horst Kessler
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3410-3417
• 全文大小：372K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

The selective targeting of the 伪v尾3 integrin subtype without affecting the structurally closely related receptor 伪5尾1 is crucial for understanding the details of their biological and pathological functions and thus of great relevance for diagnostic and therapeutic approaches in cancer treatment. Here, we present the synthesis of highly active RGD peptidomimetics for the 伪v尾3 integrin with remarkable selectivity against 伪5尾1. Incorporation of a methoxypyridine building block into a ligand scaffold and variation of different functional moieties led to 伪v尾3-antagonistic activities in the low nanomolar or even subnanomolar range. Furthermore, docking studies were performed to give insights into the binding modes of the novel compounds. The presented library comprises powerful ligands for specific addressing and blocking of the 伪v尾3 integrin subtype, thereby representing privileged tools for integrin-based personalized medicine.