Discovery of triazines as selective PDE4B versus PDE4D inhibitors
Discovery of triazines as selective PDE4B versus PDE4D inhibitors
复制标题
DOI：
10.1016/j.bmcl.2014.06.002
复制
发表时间：
2014-08-15
影响因子：
2.7
通讯作者：
Gurney, Mark E.
中科院分区：
文献类型：
--
作者：
Hagen, Timothy J.;Mo, Xuesheng;Gurney, Mark E.
在这项研究中，我们报告了一系列的三嗪衍生物，是有效的抑制剂PDE 4 B。我们还提供了一系列构效关系，证明三嗪核心可用于产生PDE 4 B与PDE 4D的亚型选择性抑制剂。高分辨率的共晶体结构显示，抑制剂与C-末端调节螺旋（CR 3）相互作用，将酶锁定在无活性的“闭合”构象。结果表明，这些化合物与催化结构域和CR 3残基都相互作用。这提供了第一个基于结构的方法来设计PDE 4 B选择性抑制剂。(C)2014爱思唯尔有限公司版权所有。
In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive 'closed' conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors. (C) 2014 Elsevier Ltd. All rights reserved.