Novel potent human ether-a-go-go-related gene (hERG) potassium channel enhancers and their in vitro antiarrhythmic activity

A variety of drugs has been reported to cause acquired long QT syndrome through inhibition of the I-Kr channel. Screening compounds in early discovery and development stages against their ability to inhibit I-Kr or the hERG channel has therefore become an indispensable procedure in the pharmaceutical industry. In contrast to numerous hERG channel blockers discovered during screening, only (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid (RPR260243) has been reported so far to enhance the hERG current. In this article, we describe several potent mechanistically distinct hERG channel enhancers. One example is PD-118057 (2-{4-[2-(3,4-dichloro-phenyl)ethyl]-phenylamino}-benzoic acid) which produced average increases of 5.5 +/- 1.1, 44.8 +/- 3.1, and 111.1 +/- 21.7% in the peak tail hERG current at 1, 3, and 10 mu M, respectively, in human embryonic kidney 293 cells. PD-118057 did not affect the voltage dependence and kinetics of gating parameters, nor did it require open conformation of the channel. In isolated guinea pig cardiomyocytes, PD-118057 showed no major effect on I-Na, I-Ca,I- L, I-K1, and I-Ks. PD-118057 shortened the action potential duration and QT interval in arterially perfused rabbit ventricular wedge preparation in a concentration-dependent manner. The presence of 3 mu M PD-118057 prevented action potential duration and QT prolongation caused by dofetilide. "Early after-depolarizations" induced by dofetilide were also completely eliminated by 3 mu M PD-118057. Although further investigation is warranted to evaluate the therapeutic value and safety profile of these compounds, our data support the notion that hERG activation by pharmaceuticals may offer a new approach in the treatment of delayed repolarization conditions, which may occur in patients with inherited or acquired long QT syndrome, congestive heart failure, and diabetes.