Blockers of the slowly delayed rectifier potassium IKs channel: potential antiarrhythmic agents.
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 I(K) was attempted to achieve this goal. After the discovery that the delayed rectifier potassium channel I(K) consists of two distinct channels, the rapidly and the slowly delayed rectifier potassium channel I(Kr) and I(Ks) respectively, blockers for these targets were looked for. But most of the described blockers of I(K), like dofetilide and D-sotalol, are highly selective and potent I(Kr) channel blockers or have only a side-activity on the I(Ks) 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 I(Ks) 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 I(Ks) 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.
Gerlach
U
U
Aventis Pharma Deutschland GmbH DI&A Chemistry Medicinal Chemistry Industrial Park Höchst, Building G 878 65926 Frankfurt am Main, Germany. uwe.Gerlach@aventis.com
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D001549:Benzamides; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology; D016757:Death, Sudden, Cardiac; D051668:Delayed Rectifier Potassium Channels; D006801:Humans; D015394:Molecular Structure; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated
D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D001569:Benzodiazepines; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman