Novel Potent Human Ether-à-Go-Go-Related Gene (hERG) Potassium Channel Enhancers and Their in Vitro Antiarrhythmic Activity

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Abstract
A variety of drugs has been reported to cause acquired long QT syndrome through inhibition of the IKr channel. Screening compounds in early discovery and development stages against their ability to inhibit IKr 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 μM, 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 INa, ICa,L, IK1, and IKs. 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 μM PD-118057 prevented action potential duration and QT prolongation caused by dofetilide. “Early after-depolarizations” induced by dofetilide were also completely eliminated by 3 μM 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.