Drug-induced QT interval prolongation can lead to the potentially life threatening arrhythmia Torsade de Pointes and is believed to result primarily from inhibition of the hERG-mediated potassium (K⁺) current in the heart. Prolongation of the QT interval of the electrocardiogram has now been observed for a number of compounds including both antiarrhythmic agents and non-cardiovascular related drugs (Pourrias et al. 1999). Therefore, an important aspect of safety pharmacology is to determine the potency of new drugs in blocking hERG channels and understand their mechanism of block. External and in-house studies have shown that certain compounds investigated seem to exhibit distinct profiles of hERG channel block. The objectives of this study were to examine the inhibition of hERG K⁺currents (I_hERG) by the novel hERG blocker, CONA-437 ([4-(3-methoxy-4-methylsulfanyl-phenoxy)-pyridin-3-ylmethyl]-dimethyl-amine), using different voltage clamp protocols and to characterize the nature of block for this type of compound. A human embryonic kidney (HEK293) cell line stably expressing the hERG K⁺ channel (Zhou et al. 1998) was used to study I_hERG at 37°C using the whole-cell patch-clamp technique. Cells were superfused with a physiological Na⁺-based extracellular solution and patch pipettes were filled with a K⁺-based intracellular solution supplemented with MgATP. Data were acquired and analysed using Axon Instruments pClamp suite of software. We have used a number of different voltage protocols in order to evoke I_hERG: a step-ramp command (at room temperature and 37°C) (hold −80mV, step +20mV for 1s, ramp to−80mV at 0.5mV/ms), a physiological ventricular action potential command and a 2-step protocol (hold−80mV, step +20mV for 2s, step−40mV). These yielded IC₅₀ values of 987nM (95% CI: 0.78—1.24μM), 1.34μM (95% CI: 0.98—1.83μM), 717nM (95% CI: 610—843nM) and 2.42μM (95% CI: 1.97—2.97μM) respectively. Apparent potency of I_hERG block by CONA-437 does not seem to vary markedly with voltage protocol or temperature. However, development of block with this compound also appears rapid. Envelope-of-tails and sustained depolarisation (−80 mV to 0 for 10 s) voltage protocols revealed that onset of I_hERG blockade was extremely rapid and occurred within 200ms.