Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate.
Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate.
复制标题
基于地芬诺酯的 Kv1.3 阻滞剂构效关系探索。
DOI：
10.1016/j.bmcl.2012.09.080
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发表时间：
2012
影响因子：
2.7
通讯作者：
Manallack,DavidT
中科院分区：
文献类型：
--
作者：
Nguyen,William;Howard,BrittanyL;Jenkins,DavidP;Wulff,Heike;Thompson,PhilipE;Manallack,DavidT
地芬诺酯是一种阿片类激动剂和抗癫痫药，最近发现它可以阻断Kv1.3钾通道，Kv1.3钾通道被认为是一系列自身免疫性疾病的潜在治疗靶点。通过从地芬诺酯结构中选择性去除官能团以及许多其他结构变化来评估这种Kv1.3阻断的分子基础。去除腈官能团并取代C-4哌啶基取代基产生了几种具有亚微摩尔IC 50值的化合物。
Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 blockade was assessed by the selective removal of functional groups from the structure of diphenoxylate as well as a number of other structural variations. Removal of the nitrile functional group and replacement of the C-4 piperidinyl substituents resulted in several compounds with submicromolar IC50values.