New antiarrhythmic agents. 3. Primary beta-amino anilides

Area of Science:

• Medicinal Chemistry
• Pharmacology

Background:

• Cardiac arrhythmias are a significant cause of mortality.
• Existing antiarrhythmic drugs have limitations, necessitating the development of new therapeutic agents.
• Beta-amino anilides represent a class of compounds with potential antiarrhythmic activity.

Purpose of the Study:

• To synthesize and pharmacologically evaluate novel primary beta-amino anilides.
• To compare the efficacy and safety of these novel compounds with established drugs like tocainide and lidocaine.
• To identify lead compounds with improved antiarrhythmic potency and reduced central nervous system (CNS) toxicity.

Main Methods:

• Synthesis of beta-amino anilides via acylation of anilines with bromoacyl chlorides or acryloyl chlorides, followed by amination or hydrazinolysis.
• Evaluation of antifibrillatory activity in a mouse model of chloroform-induced fibrillation.
• Assessment of antiarrhythmic effects against ventricular arrhythmias in a dog model of myocardial infarction.
• Comparative analysis of CNS toxicity.

Main Results:

• All synthesized beta-amino anilides exhibited antifibrillatory activity.
• Several compounds demonstrated greater potency than tocainide.
• Compound 3-amino-2',6'-butyroxylidide (38) showed superior potency and reduced CNS toxicity compared to tocainide in canine models.
• The synthetic routes provided efficient access to the target beta-amino anilides.

Conclusions:

• Novel beta-amino anilides possess significant potential as antiarrhythmic agents.
• Compound 3-amino-2',6'-butyroxylidide (38) is a promising candidate for further development as an oral antiarrhythmic drug due to its enhanced efficacy and safety profile.
• The study validates beta-amino anilides as a valuable scaffold for antiarrhythmic drug discovery.