Key result
Novel phenylpyridine derivative 24i demonstrates ~2-fold higher antiarrhythmic potency than mexiletine in mice.
Why the study?
New disubstituted phenylpyridine derivatives were synthesized to evaluate their antiarrhythmic effects against chloroform-induced ventricular arrhythmias in mice.
Warrants further preclinical development of these derivatives; leaves open clinical translation from animal data.
A series of disubstituted phenylpyridine derivatives was synthesized and their antiarrhythmic effects against chloroform-induced ventricular arrhythmias in mice were examined. Among them, 2- and 3-[2-(3-aminobutyramido)-4-(2,2,2-trifluroethoxy)phenyl]pyri dines (23h, 24h) and 3-[2-(3-aminobutyramido)-4-ethoxyphenyl]pyridine (24i) showed potent antiarrhythmic activity. They had approximately twice the potency of mexiletine (III). Compound 24i was selected from this series as a candidate for further development; it was found to have a class I B electrophysiological character and to show a slow kinetic rate-dependent block (RDB) of the sodium channel in cardiac muscle.
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Shigyo et al. (1993) studied Chloroform-induced ventricular arrhythmias. Disubstituted phenylpyridine derivatives (e.g., compound 24i) vs. Mexiletine was evaluated on Antiarrhythmic activity. Disubstituted phenylpyridine derivatives, particularly compound 24i, showed potent antiarrhythmic activity in mice with approximately twice the potency of mexiletine.
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