Blockers of the Slowly Delayed Rectifier Potassium IKs Channel: Potential Antiarrhythmic Agents

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Abstract
Prolongation of the cardiac action potential and the effective refractory period is a proven principle to prevent cardiac arrhythmias, especially under conditions when the action potential is shortened. Several approaches have been made to achieve this effect selectively and without proarrhythmic side effects. Besides the blockade of the cardiac sodium channel, blockade of the delayed rectifier potassium channel IK was attempted to achieve this goal. After the discovery that the delayed rectifier potassium channel IK consists of two distinct channels, the rapidly and the slowly delayed rectifier potassium channel IKr and IKs respectively, blockers for these targets were looked for. But most of the described blockers of IK, like dofetilide and D-sotalol, are highly selective and potent IKr channel blockers or have only a side-activity on the IKs channel, as described for azimilide. These compounds have shown their efficacy in terminating atrial or ventricular fibrillation under certain circumstances, but they also have shown high risk to induce arrhythmias by themselves. It was speculated that IKs channel blockers may be free of this unwanted effect and several companies put effort to find compounds selective for this novel target. The strategies to find potent and selective IKs channel will be reviewed as well as their first results in in-vitro and in-vivo models of arrhythmia. As side effects are a potential danger for this ubiquitous channel, also the safety studies with these compounds will be summarized.

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