New antiarrhythmic agents. 1. Primary alpha-amino anilides

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Cardiovascular Research

Background:

• Alpha-amino anilides are a class of compounds with potential therapeutic applications.
• Cardiac arrhythmias, such as fibrillation, represent a significant clinical challenge.
• Understanding structure-activity relationships is crucial for developing effective antiarrhythmic drugs.

Purpose of the Study:

• To synthesize and characterize thirty-two alpha-amino anilides.
• To evaluate the antifibrillatory and toxic effects of these compounds in mice.
• To assess the antiarrhythmic activity of selected compounds in a canine model of myocardial infarction.

Main Methods:

• Synthesis of diverse alpha-amino anilides with variations in aromatic ring and alpha-position substituents.
• Assessment of protection against chloroform-induced cardiac fibrillation in a murine model.
• Evaluation of compound toxicity in mice.
• Testing of eleven compounds for antiarrhythmic effects in dogs with surgically induced myocardial infarction.

Main Results:

• Substitution with alkyl or aryl groups at the alpha position generally enhanced antifibrillatory activity in mice.
• Increased potency of antifibrillatory effects was frequently associated with increased toxicity.
• Eleven tested compounds demonstrated antiarrhythmic activity in the canine myocardial infarction model.
• 2-Aminopropiono-2',6'-xylidide (tocainide) emerged as a compound with significant potential.

Conclusions:

• Structural modifications of alpha-amino anilides can modulate antifibrillatory and toxic properties.
• Alpha-substitution is a key factor in enhancing antiarrhythmic efficacy.
• Tocainide exhibits promising antiarrhythmic properties suitable for further clinical investigation.