Synthesis and pharmacological studies of N-substituted 6-[(2-aminoethyl)amino]-1,3-dimethyl-2,4(1H,3H)-pyrimidinediones, novel class III antiarrhythmic agents

• Published in: Journal of medicinal chemistry Vol. 35; no. 18; pp. 3325 - 3330
• Main Authors: Katakami, Tsutomu, Yokoyama, Tatsuro, Miyamoto, Michihiko, Mori, Haruki, Kawauchi, Nobuya, Nobori, Tadahito, Sannohe, Kunio, Kaiho, Tatsuo, Kamiya, Joji
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.09.1992; Amer Chemical Soc
• Subjects: Animals; Anti-Arrhythmia Agents - chemical synthesis; Anti-Arrhythmia Agents - pharmacology; Chemistry; Chemistry, Medicinal; Dogs; Exact sciences and technology; Female; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; In Vitro Techniques; Life Sciences & Biomedicine; Male; Organic chemistry; Pharmacology & Pharmacy; Preparations and properties; Pyrimidinones - chemical synthesis; Pyrimidinones - pharmacology; Science & Technology; Structure-Activity Relationship; VENTRICULAR ARRHYTHMIAS; SUPPRESSION; CARDIAC ELECTROPHYSIOLOGICAL ACTIVITY; Diamine; In vivo; Structure activity relation; Nitrogen heterocycle; Six membered ring; In vitro; Alkylation; Antiarrhythmia agent
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00096a003

A series of (6-[(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.2