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The slowly (IKs) and rapidly (IKr) activating delayed rectifier K+ currents play important roles in cardiac ventricular repolarization. Compared with IKr, however, IKs has important distinguishing characteristics, including ß-adrenergic receptor stimulation and accumulation at rapid rates that may impart significant therapeutic relevance. Therefore, development of selective IKs inhibitors has been pursued as a strategy for providing potentially safer and more effective Class III antiarrhythmic agents and pharmacological tools for elucidating the normal physiological and potential pathological role of IKs in cardiac repolarization. We have identified a series of 3-Acylamino-1,4 benzodiazepines that are very potent and selective inhibitors of IKs. A representative compound, L-768,673 (1) (IC50∼8nM), has been extensively characterized for its pharmacologic activity. L-768,673 concentration-dependently prolongs action potential duration in a frequency-independent manner in vitro, but decreases transmural dispersion of refractoriness, a risk factor for arrhythmia induction. In conscious dogs, L-768,673 administered IV (0.3-100 μg / kg) and PO (0.03-1 mg / kg) elicits consistent but limited (5-15%) QTc prolongation, and increases ventricular refractory period more at fast than at slow pacing rates, indicating a “forward” rate-dependence in vivo. In an anesthetized canine model of anterior myocardial infarction, IKs blockers suppress the development of ischemic ventricular fibrillation at intravenous doses that minimally prolong the QT interval. IKs blockers display an interesting and intriguing profile of effects on cardiac electrophysiologic parameters that differ in remarkable ways from other selective Class III agents such as IKr blockers. It remains to be determined if these properties can be exploited clinically to provide more effective and safer treatment of cardiac arrhythmias.
Merck Research Laboratories, WP45A-201, 770 Sumneytown Pike, West Point, PA 19486, USA.
Publication date: January 1, 2004
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Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.