Synthesis and structure-activity relationships of a new series of antiarrhythmic agents: monobasic derivatives of disobutamide.
Analogues of the dibasic antiarrhythmic agent disobutamide (2) were prepared and evaluated for antiarrhythmic efficacy, myocardial depression, and anticholinergic activity. The replacement of an isopropyl group in disobutamide by an acetyl group led to the monobasic analogue SC-40230, 7a, which demonstrated good antiarrhythmic activity accompanied by less myocardial depressant and anticholinergic activities. In addition, it did not induce clear cytoplasmic vacuoles as did the parent compound. SC-40230 was chosen from among other analogues as a candidate for clinical evaluation. Other compounds prepared and evaluated included indolizidinones and a secondary amine isomer of disobutamide.
Desai
B N
BN
Cardiovascular Diseases Research Department, G.D. Searle and Company, Skokie, Illinois 60077.
Fowler
K W
KW
Chorvat
R J
RJ
Frederick
L G
LG
Hatley
F R
FR
Rorig
K J
KJ
Garthwaite
S M
SM
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D004285:Dogs; D004341:Drug Evaluation; D006863:Hydrogen-Ion Concentration; D007536:Isomerism; D010880:Piperidines; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D011976:Receptors, Muscarinic; D015222:Sodium Channels; C030153:disobutamide