Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany.
Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany.
Eur J Med Chem. 2020 Jan 1;185:111766. doi: 10.1016/j.ejmech.2019.111766. Epub 2019 Oct 9.
In the present article we describe the creation of a small carboranylcarboxamide compound library followed by a screening campaign at the soluble epoxide hydrolase (sEH). We identified meta-carboranyl alkylamides, -anilides, and -benzylamides as potent sEH inhibitors. Furthermore, we optimized the scaffolds and we derived structure-activity relationships. The most potent benzylamide 33 (MS1) was similar to a previously reported adamantane derivative and gave an IC value of 0.07 μM for meta- and 0.08 μM for para-carborane at isolated sEH. The ortho-derivative suffered deboronation. The results underline the potential of carboranes as non-natural 3-D pharmacophores to extend the chemical space in drug discovery.
在本文中，我们描述了一种小型碳硼烷羧酰胺化合物库的创建，随后对可溶型环氧水解酶（sEH）进行了筛选实验。我们发现间位碳硼烷烷基酰胺、-苯胺和-苄基酰胺是强效的 sEH 抑制剂。此外，我们对支架进行了优化，并得出了构效关系。最有效的苄基酰胺 33（MS1）与先前报道的金刚烷衍生物相似，对间位和对位碳硼烷的 sEH 的 IC 值分别为 0.07 μM 和 0.08 μM。邻位衍生物发生去硼化反应。这些结果强调了碳硼烷作为非天然 3-D 药效团的潜力，可在药物发现中扩展化学空间。
