טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentLevy Ofra
SubjectThe Design and Synthesis of Novel Ventricular Defibrillating
Agents
DepartmentDepartment of Chemistry
Supervisors Professor Emeritus Ehud Keinan
Dr. Mordechai Erez


Abstract

Sudden cardiac death (SCD) is the major cause of human mortality among adults, mainly among patients suffering from either coronary heart disease or congested heart failure. It is commonly accepted that ventricular arrhythmia, such as ventricular tachycardia and ventricular fibrillation (VF), plays the major role in SCD. A new therapeutic approach has been proposed, suggesting that defibrillating drugs enhance the heart’s ability to defibrillate spontaneously. Novel dibenzoazepine and 11-oxo-dibenzodiazepine derivatives have been synthesized and examined for their potential activity as defibrillating agents in in-vivo and ex-vivo models. Structure activity relationship (SAR) study was proceed. The SAR studies point at higher activity of derivatives of dibenzoazepine in comparison with those related to 11-oxo-dibenzodiazepine. These studies also highlight the superiority of the 3-amino-2-hydroxyalkyl side chains. Enantioselectivity was observed for these derivatives, the S-(-) enantiomer was found to be the most effective ventricular defibrillating drug candidate. All active analogs exhibit significant in-vivo defibrillatory activity with no observed changes in ECG either before or after the VF event. Some of these compounds also exhibit antifibrillatory activity by elevating the fibrillation threshold potential, all suggesting that such drugs could be used to treat VF either by themselves or together with electrical defibrillators.