Pharmacological modulation of I(Ks): potential for antiarrhythmic therapy.
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)~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 micro g/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.
Salataa
Joseph J
JJ
Departmentof Preclinical Safety Evaluation, Merck Research Laboratories, West Point, PA 19486, USA. joseph_salata@merck.com
Selnickb
Harold G
HG
Lynch
Joseph J
JJ
D000081:Acetamides / Q000138:chemical synthesis / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000145:classification / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated; D012032:Refractory Period, Electrophysiological / Q000187:drug effects / Q000502:physiology
D000081:Acetamides; D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D001570:Benzodiazepinones; D051668:Delayed Rectifier Potassium Channels; C109598:L 768673; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D001569:Benzodiazepines