Discovery of 'molecular switches' within a GIRK activator scaffold that afford selective GIRK inhibitors.
Discovery of 'molecular switches' within a GIRK activator scaffold that afford selective GIRK inhibitors.
复制标题
在 GIRK 激活剂支架内发现“分子开关”，可提供选择性 GIRK 抑制剂。
DOI：
10.1016/j.bmcl.2013.06.023
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发表时间：
2013
影响因子：
2.7
通讯作者：
Lindsley,CraigW
中科院分区：
文献类型：
--
作者：
Wen,Wandong;Wu,Wenjun;Romaine,IanM;Kaufmann,Kristian;Du,Yu;Sulikowski,GaryA;Weaver,CDavid;Lindsley,CraigW
这封信描述了一种基于强效、有效和选择性GIRK 1/2激活剂的多维SAR活动（与GIRK 1/4相比为10倍，对不含GIRK 1的GIRK、GIRK 2或GIRK 2/3无活性）。通过迭代平行合成的进一步化学优化工作确定了多个“分子开关”，这些开关调节了从激活剂到抑制剂的药理学模式，以及产生了GIRK 1/2和GIRK 1/4的不同选择性特征。重要的是，这些化合物都对含有非GIRK 1的GIRK通道无活性。然而，SAR具有挑战性，因为细微的结构修饰对药理学模式以及GIRK 1/2和GIRK 1/4通道选择性都有很大影响。
This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator (∼10-fold versus GIRK1/4 and inactive on nonGIRK 1-containing GIRKs, GIRK 2 or GIRK2/3). Further chemical optimization through an iterative parallel synthesis effort identified multiple ‘molecular switches’ that modulated the mode of pharmacology from activator to inhibitor, as well as engendering varying selectivity profiles for GIRK1/2 and GIRK1/4. Importantly, these compounds were all inactive on nonGIRK1 containing GIRK channels. However, SAR was challenging as subtle structural modifications had large effects on both mode of pharmacology and GIRK1/2 and GIRK1/4 channel selectivity.