Novel antiarrhythmic compounds with combined class IB and class III mode of action.
Cardiac arrhythmias represent a major area of cardiovascular research, and for drug therapy, a large choice of antiarrhythmic agents have been available. However, clinical trials with antiarrhythmic drugs have recently indicated that serious side effects may considerably limit the use of various antiarrhythmic agents, in particular, for preventing arrhythmia-related mortality. Amiodarone with its complex mode of action, while exerting a strong and favorable antiarrhythmic action, posseses extracardiac untoward side effects originating from its chemical structure. In this paper, we report on our attempt to develop conceptually new, therapeutically valuable antiarrhythmic compounds, in which Class I/B and Class III features were combined into single molecules bearing no structural resemblance to amiodarone. Synthesis and pharmacological screening of series of N-(phenylalkyl)-N-(phenoxyalkyl)amines led us to discover some new promising compounds with the required dual mode of action. GYKI-16638, selected for further investigation, was also found to possess a remarkable in vivo antiarrhythmic effect, and it is now considered as a safe new antiarrhythmic drug candidate.
Mátyus
Péter
P
Department of Organic Chemistry, Semmelweis University, Budapest, Hungary. matypet@szerves.sote.hu
Varga
Ildikó
I
Rettegi
Tivadar
T
Simay
Antal
A
Kállay
Nikolett
N
Károlyházy
László
L
Kocsis
Akos
A
Varró
András
A
Pénzes
István
I
Papp
Julius Gy
JG
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000145:classification / Q000494:pharmacology*; D003327:Coronary Disease / Q000188:drug therapy; D051668:Delayed Rectifier Potassium Channels; D015195:Drug Design; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects; D008801:Mexiletine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D010627:Phenethylamines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D008801:Mexiletine; C420122:GYKI 16638; D013015:Sotalol