IKr channel blockers: novel antiarrhythmic agents.
There have been extensive efforts to develop I(Kr) channel blockers as a new antiarrhythmic agent for atrial or ventricular fibrillation, since it was demonstrated that selective blockade of the rapidly activating delayed rectifier K+ channel (I(Kr)) in the heart is not deleterious for the total mortality in fatal ventricular arrhythmia patients. Among them, dofetilide and KCB-328 blocks the I(Kr) specifically. Therefore, it increases the action potential duration (APD) selectively. Ibutilide, trecetilide, nifekalant, dronedarone, BRL-32872, H345/52 and ersentilide block the I(Kr). However, they modify also other cardiac channels or receptors. The frequency dependence of the compounds in prolonging the APD varies from the strong reversed tendency of dofetilide to the relatively neutral profile of KCB-328 and BRL-32872. Every compound reported so far has a proarrhythmic potential of torsade de pointes induction under certain conditions, although depending on the structure, the intensity may be somewhat different. In the coming decade, efforts to improve the reverse frequency dependence profile of the I(Kr) blockers by optimizing the onset and recovery time constant of the HERG block (e.g. KCB-328, vesnarinone) or the balance between the block of I(Kr) and Ca++ channels in the heart (e.g. BRL-32872, H 345/52) to eliminate the proarrhythmic potential of the currently known I(Kr) blockers are warranted. Further trials are also needed to discover more favorable compounds with multiple receptors including I(Kr) (e.g. nifekalant, dronedarone) for treating ventricular arrhythmias.
Department of Pharmacology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Seoul, Korea.
K
K
Lee
J Y
JY
Park
P D
PD
Ryu
L S
LS
Kwon
H Y
HY
Kim
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000401:mortality; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000139:chemically induced
C112304:1-(2-amino-4-methanesulfonamidophenoxy)-2-(N-(3,4-dimethoxyphenethyl)-N-methylamino)ethane; D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013449:Sulfonamides