Pharmacological modulation of I-Ks: Potential for antiarrhythmic therapy

Author:

Salata, JJ  Selnick, HG  Lynch, JJ  

Journal:

CURRENT MEDICINAL CHEMISTRY

Issue Date:

2004

Abstract(summary):

The Slowly (I-Ks) and rapidly (I-Kr) activating delayed rectifier K+ currents play important roles in cardiac ventricular repolarization. Compared with I-Kr however, I-Ks has important distinguishing characteristics, including beta-adrenergic receptor stimulation and accumulation at rapid rates that may impart significant therapeutic relevance. Therefore, development of selective I-Ks 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 I-Ks in cardiac repolarization. We have identified a series of 3-Acylamino-1,4 benzodiazepines that are very potent and selective inhibitors Of I-Ks. A representative compound, L-768.673 (1) (IC(50)similar to8nM), 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 mug/kg) and PO (0.03-1 mg/kg) elicits consistent but limited (5-15%) QT(c) 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, I-Ks blockers suppress the development of ischemic ventricular fibrillation at intravenous doses that minimally prolong the QT interval. I-Ks 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 I-Kr blockers. It remains to be determined if these properties can be exploited clinically to provide more effective and safer treatment of cardiac arrhythmias.

Page:

29---44