Synthesis, cardiac electrophysiology, and beta-blocking activity of novel arylpiperazines with potential as class II/III antiarrhythmic agents.
A series of novel arylpiperazines have been prepared in an attempt to incorporate both class II (beta-receptor blocking) and class III antiarrhythmic properties in a single molecule. The key step in the preparation of the new compounds involves a regioselective heterocyclic ring formation. All but four compounds significantly prolonged action potential duration in canine cardiac Purkinje fibers (class III activity). All but one of the compounds demonstrated beta-receptor affinity in a competitive binding assay and three had beta 1-receptor selectivity. Compared to sotalol, a reference class II/III agent, arylpiperazine 7a (4-[(methylsulfonyl)amino]-N-[(4- phenylpiperazin-2-yl)methyl]benzamide) demonstrated beta 1-selectivity and was 1 order of magnitude more potent in the in vitro class III and the beta 1-receptor screens. Compound 7a was evaluated further and found to be effective in preventing programmed electrical stimulation-induced arrhythmias in conscious dogs (class III activity) and against epinephrine-induced arrhythmias in halothane anesthetized dogs (class II activity).
Phillips
G B
GB
Department of Medicinal Chemistry, Berlex Laboratories, Inc., Cedar Knolls, New Jersey 07927.
Morgan
T K
TK
Lumma
W C
WC
Gomez
R P
RP
Lind
J M
JM
Lis
R
R
Argentieri
T
T
Sullivan
M E
ME
D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000209:etiology; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001667:Binding, Competitive; D004285:Dogs; D004558:Electric Stimulation; D004594:Electrophysiology; D004837:Epinephrine; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013015:Sotalol / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D010879:Piperazines; D011943:Receptors, Adrenergic, beta; C073197:4-((methylsulfonyl)amino)-N-((4-phenylpiperazin-2-yl)methyl)benzamide; D013015:Sotalol; D004837:Epinephrine