Potent Kv1.3 inhibitors from correolide - modification of the C18 position

被引：14

作者：

Bao, JM

Miao, SW

Kayser, F

Kotliar, AJ

Baker, RK

Dossa, GA

Felix, JP

Bugianesi, RM

Slaughter, RS

Kaczorowski, GJ

Garcia, ML

Ha, SN

Castonguay, L

Koo, GC

Shah, K

Springer, MS

Staruch, MJ

Parsons, WH

Rupprecht, KM

机构：

[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA

[2] Merck Res Labs, Dept Ion Channels, Rahway, NJ 07065 USA

[3] Merck Res Labs, Dept Mol Syst, Rahway, NJ 07065 USA

[4] Merck Res Labs, Dept Immunol Res, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 02期

关键词：

potassium channel; Kv1.3; correolide; ion channel blocker; T cell; immunosuppressant;

D O I：

10.1016/j.bmcl.2004.10.058

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Kv1.3, the voltage-gated potassium channel in human T cells, represents a new target for treating immunosuppression and autoimmune diseases. Correolide (1), a pentacyclic natural product, is a potent and selective Kv1.3 channel blocker. Simplification of correolide via removal of its E-ring generates enone 4, whose modification produced a new series of tetracyclic Kv1.3 blockers. The structure-activity relationship for this class of compounds in two functional assays, Rb_Kv and human T cell proliferation, is presented herein. The most potent analog 43 is 15-fold more potent than correolide as inhibitor of human T cell proliferation. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：447 / 451

页数：5

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