Novel reversible methionine aminopeptidase-2 (MetAP-2) inhibitors based on purine and related bicyclic templates

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• 作者：Timo Heinrich^a ; ^{timo.heinrich@merckgroup.com} ; Hans-Peter Buchstaller^a ; Bertram Cezanne^b ; Felix Rohdich^c ; Jö ; rg Bomke^a ; Manja Friese-Hamim^d ; Mireille Krier^a ; Thorsten Knö ; chel^e ; Djordje Musil^a ; Birgitta Leuthner^a ; Frank Zenke^f
• 关键词：MetAP2 ; Methionine aminopeptidase 2 ; Metalloprotease ; Purine
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：551-556
• 全文大小：2339 K
• 卷排序：27

文摘

The natural product fumagillin 1 and derivatives like TNP-470 2 or beloranib 3 bind to methionine aminopeptidase 2 (MetAP-2) irreversibly. This enzyme is critical for protein maturation and plays a key role in angiogenesis. In this paper we describe the synthesis, MetAP-2 binding affinity and structural analysis of reversible MetAP-2 inhibitors. Optimization of enzymatic activity of screening hit 10 (IC50: 1 μM) led to the most potent compound 27 (IC50: 0.038 μM), with a concomitant improvement in LLE from 2.1 to 4.2. Structural analysis of these MetAP-2 inhibitors revealed an unprecedented conformation of the His339 side-chain imidazole ring being co-planar sandwiched between the imidazole of His331 and the aryl-ether moiety, which is bound to the purine scaffold. Systematic alteration and reduction of H-bonding capability of this metal binding moiety induced an unexpected 180° flip for the triazolo[1,5-a]pyrimdine bicyclic template.