The antiarrhythmic drug BRL-32872.
BRL-32872 is a new antiarrhythmic drug with balanced class-III and class-IV actions as categorized by the Vaughan-Williams classification. BRL-32872 blocks the rapid component of the cardiac delayed rectifier potassium channel IK(r) (IC(50) = 28 nM) and its molecular correlate HERG ("Human-ether-a-go-go related gene," IC(50) of 19.8 nM in cell lines) at low concentrations. It also inhibits the L-type calcium current (ICa) at higher concentrations (IC(50) = 2.8 microM). This dual concentration-dependent profile of action at higher concentrations may possibly prevent "torsades de pointes" ventricular arrhythmias, which is a dangerous side effect of many other class-III antiarrhythmic drugs. With BRL-32872, an excessive prolongation of the action potential duration and consecutive QTc prolongation is prevented by a concentration-dependent increase of calcium channel block, resulting in the so-called "bell-shaped" profile of antiarrhythmic drug action. BRL-32872 is very effective in the treatment of ventricular arrhythmias in animal models of cardiac ischemia. In the ischemic hearts of animals the drug significantly reduced early afterdepolarization and ventricular tachycardia. The antiarrhythmic effect of BRL-32872 has not yet been demonstrated in humans.
Karle
Christoph A
CA
Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.
Thomas
Dierk
D
Kiehn
Johann
J
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D017202:Myocardial Ischemia / Q000150:complications; D009206:Myocardium / Q000378:metabolism*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000209:etiology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C094198:BRL 32872