New drugs targeting the cardiac ultra-rapid delayed-rectifier Current(IKur):: Rationale, pharmacology and evidence for potential therapeutic value

被引：76

作者：

Ford, John W. ^{[1
]}

Milnes, James T. ^{[1
]}

机构：

[1] Xention Ltd, Cambridge CB22 3EG, England

来源：

JOURNAL OF CARDIOVASCULAR PHARMACOLOGY | 2008年 / 52卷 / 02期

关键词：

atrial fibrillation; atrial flutter; I-Kur; Kv1.5; ultra-rapid delayed rectifier; cardiac; heart; arrhythmia;

D O I：

10.1097/FJC.0b013e3181719b0c

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

There is a clear unmet medical need for new pharmacologic therapies for the treatment of atrial fibrillation (AF) with improved efficacy and safety. This article reviews the development of new and novel Kv1.5/ultra-rapid delayed-rectifier current (I-Kur) inhibitors and presents evidence that Kv1.5 modulation provides an atrial-selective mechanism for treating AF Academia and industry have invested heavily in Kv1.5 (> 500 scientific publications and > 50 patients published since 1993); however, to realize the full value of this therapeutic drug clinical efficacy and safety data are required for a selective Kv1.5 modulator. The reward for demonstrating clinical efficacy and safety in a pivotal Phase 3 trial, on regulatory approval, is "first in class" status.

引用

收藏

页码：105 / 120

页数：16

相关论文

共 139 条

[101]

Rivard L, 2005, HEART RHYTHM, V2, pS180

[102] THE VOLTAGE-DEPENDENT K+ CHANNEL (KV1.5) CLONED FROM RABBIT HEART AND FACILITATION OF INACTIVATION OF THE DELAYED RECTIFIER CURRENT BY THE RAT BETA-SUBUNIT [J].

SASAKI, Y ;

ISHII, K ;

NUNOKI, K ;

YAMAGISHI, T ;

TAIRA, N .

FEBS LETTERS, 1995, 372 (01) :20-24

[103] Blockade of atrial-specific K+-currents increases atrial but not ventricular contractility by enhancing reverse mode Na+/Ca2+-exchange [J].

Schotten, Ulrich ;

de Haan, Sunniva ;

Verheule, Sander ;

Harks, Erik G. A. ;

Frechen, Dirk ;

Bodewig, Eva ;

Greiser, Maura ;

Rarn, Rashmi ;

Maessen, Jos ;

Kelm, Malte ;

Allessie, Maurits ;

Van Wagoner, David R. .

CARDIOVASCULAR RESEARCH, 2007, 73 (01) :37-47

[104] Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function [J].

Schram, G ;

Pourrier, M ;

Melnyk, P ;

Nattel, S .

CIRCULATION RESEARCH, 2002, 90 (09) :939-950

[105] Prednisone prevents atrial fibrillation promotion by atrial tachycardia remodeling in dogs [J].

Shiroshita-Takeshita, A ;

Brundel, BJJM ;

Lavoie, J ;

Nattel, S .

CARDIOVASCULAR RESEARCH, 2006, 69 (04) :865-875

[106]

Shiroshita-Takeshita A., 2006, HEART RHYTHM, V3, pS183, DOI [10.1016/j.hrthm.2006.02.549, DOI 10.1016/J.HRTHM.2006.02.549]

[107] The plateau outward current in canine ventricle, sensitive to 4-aminopyridine, is a constitutive contributor to ventricular repolarization [J].

Sridhar, A. ;

da Cunha, D. N. Q. ;

Lacombe, V. A. ;

Zhou, Q. ;

Fox, J. J. ;

Hamlin, R. L. ;

Carnes, C. A. .

BRITISH JOURNAL OF PHARMACOLOGY, 2007, 152 (06) :870-879

[108] Atrial fibrillation: an emerging epidemic? [J].

Steinberg, JS .

HEART, 2004, 90 (03) :239-240

[109] Comparison of potent Kv1.5 potassium channel inhibitors reveals the molecular basis for blocking kinetics and binding mode [J].

Strutz-Seebohm, Nathalie ;

Gutcher, Ilona ;

Decher, Niels ;

Steinmeyer, Klaus ;

Lang, Florian ;

Seebohm, Guiscard .

CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, 2007, 20 (06) :791-800

[110] In vivo antiarrhythmic and cardiac electrophysiologic effects of a novel diphenylphosphine oxide IKur blocker (2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide [J].

Stump, GL ;

Wallace, AA ;

Regan, CP ;

Lynch, JJ .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 315 (03) :1362-1367

← 5 6 7 8 9 10 11 12 13 14 →