Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate

被引：11
|
作者：
Nguyen, William [1 ]
Howard, Brittany L. [1 ]
Jenkins, David P. [2 ]
Wulff, Heike [2 ]
Thompson, Philip E. [1 ]
Manallack, David T. [1 ]
机构：
[1] Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia
[2] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 23期
关键词：
Kv1.3; Ion channel blockers; Autoimmune disease; Electrophysiology; Medicinal chemistry; MEMORY T-CELLS; AUTOIMMUNE-DISEASES; POTASSIUM CHANNELS; PSORIASIS; SUPPRESSION; TARGETS; PAP-1; SKIN; ION;
D O I：
10.1016/j.bmcl.2012.09.080
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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 IC50 values. (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码：7106 / 7109
页数：4
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