Synthesis and pharmacological studies of N-substituted 6-[(2-aminoethyl)amino]-1,3-dimethyl-2,4(1H,3H)-pyrimidinediones, novel class III antiarrhythmic agents.
A series of 6-[(2-aminoethyl)amino]-1,3-dimethyl-2,4(1H,3H)- pyrimidinedione derivatives were synthesized and studied for their class III electrophysiological activity and class II (beta-blocking) effects in in vitro and in vivo models. Structure-activity relationships are discussed for a series of compounds. Several members of this series prolonged the action potential duration at 75% repolarization of isolated canine Purkinje fibers and were 10-30-fold more potent than d-sotalol. 1,3-Dimethyl-6-[[2-[N-[3-(4-nitrophenyl)propyl]-N- (hydroxyethyl)amino]ethyl]amino]-2,4-(1H,3H)-pyrimidinedione (40), is one of the most potent compounds in this series.
Katakami
T
T
Medicinal Chemistry Department, Mitsui Toatsu Chemicals Inc., Chiba, Japan.
Yokoyama
T
T
Miyamoto
M
M
Mori
H
H
Kawauchi
N
N
Nobori
T
T
San-nohe
K
K
Kaiho
T
T
Kamiya
J
J
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D011744:Pyrimidinones