4-Phenoxybutoxy-substituted heterocycles--a structure-activity relationship study of blockers of the lymphocyte potassium channel Kv1.3.
4-Phenoxybutoxy-substituted heterocycles--a structure-activity relationship study of blockers of the lymphocyte potassium channel Kv1.3.
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DOI：
10.1016/j.ejmech.2008.10.033
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发表时间：
2009-05
影响因子：
6.7
通讯作者：
Wulff, Heike
中科院分区：
文献类型：
--
作者：
Bodendiek, Silke B.;Mahieux, Cedrick;Haensel, Wolfram;Wulff, Heike
The voltage-gated potassium channel Kv1.3 constitutes an attractive pharmacological target for the treatment of effector memory T cell-mediated autoimmune diseases such as multiple sclerosis and psoriasis. Using 5-methoxypsoralen (5-MOP, 1), a compound isolated from Ruta graveolens, as a template we previously synthesized 5-(4-phenoxybutoxy)psoralen (PAP-1, 2) which inhibits Kv1.3 with an IC50 of 2 nM. Since PAP-1 is more than 1000-fold more potent than 5-MOP, we here investigated whether attaching a 4-phenoxybutoxy side-chain to other heterocyclic systems would also produce potent Kv1.3 blockers. While 4-phenoxybutoxy substituted quinolines, quinazolines and phenanthrenes were inactive, 4-phenoxybutoxy substituted quinolinones, furoquinolines, coumarins or furochromones inhibited Kv1.3 with IC50s of 150 nM to 10 µM in whole-cell patch-clamp experiments. Our most potent new compound is 4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromene-7-thione (73, IC50 17 nM), in which the carbonyl oxygen of PAP-1 is replaced by sulfur. Taken together, our results demonstrate that the psoralen system is a crucial part of the pharmacophore of phenoxyalkoxypsoralen-type Kv1.3 blockers.
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影响因子：
7.3
作者：
Harvey, AJ;Baell, JB;Wulff, H
通讯作者：
Wulff, H
影响因子：
2.1
作者：
NARASIMHAN, NS;MALI, RS
通讯作者：
MALI, RS
影响因子：
6.5
作者：
Azam, Philippe;Sankaranarayanan, Ananthakrishnan;Wulff, Heike
通讯作者：
Wulff, Heike
影响因子：
3.6
作者：
Beeton, C;Pennington, MW;Chandy, KG
通讯作者：
Chandy, KG
影响因子：
0.8
作者：
BOHUSLAVIZKI, KH;HINCKKNEIP, C;REIMERS, A
通讯作者：
REIMERS, A