Design and bio-evaluation of indole derivatives as potent Kv1.5 inhibitors

被引：22

作者：

Guo, Xiaoke ^{[1
,2
]}

Yang, Qian ^{[1
,2
]}

Xu, Jing ^{[4
]}

Zhang, Li ^{[4
]}

Chu, Hongxi ^{[1
,3
]}

Yu, Peng ^{[4
]}

Zhu, Yingying ^{[4
]}

Wei, Jinglian ^{[3
]}

Chen, Weilin ^{[3
]}

Zhang, Yaozhong ^{[3
]}

Zhang, Xiaojin ^{[1
]}

Sun, Haopeng ^{[1
,2
,3
]}

Tang, Yiqun ^{[4
]}

You, Qidong ^{[1
,2
]}

机构：

[1] China Pharmaceut Univ, Jiang Su Key Lab Drug Design & Optimizat, Nanjing 210009, Jiangsu, Peoples R China

[2] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China

[3] China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 210009, Jiangsu, Peoples R China

[4] China Pharmaceut Univ, Res Div Pharmacol, Nanjing 210009, Jiangsu, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 21期

关键词：

Atrial fibrillation (AF); Kv1.5; Indole derivatives; Structure-activity relationship (SAR); ATRIAL-FIBRILLATION THERAPY; ANTIARRHYTHMIC-DRUG THERAPY; HERG POTASSIUM CHANNELS; VENTRICULAR MYOCYTES; I-KUR; BLOCKERS; AGENT; STRATEGIES; MANAGEMENT; AMIDES;

D O I：

10.1016/j.bmc.2013.08.041

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Atrial fibrillation (AF) is one of the common arrhythmias that threaten human health. Kv1.5 potassium channel is reported as an efficacious and safe target for the treatment of AF. In this paper, we designed and synthesized three series of compounds through modifying the lead compound RH01617 that was screened out by the pharmacophore model we reported earlier. All of the compounds were evaluated by the whole-patch lamp technology and most of them possessed potent inhibitory activities against Kv1.5. Compounds IIIi and IIIl were evaluated for the target selectivity as well as the pharmacodynamic effects in an isolated rat model. Due to the promising pharmacological behavior, compound IIIl deserves further pharmacodynamic and pharmacokinetic evaluations. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：6466 / 6476

页数：11

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