title: Electrophysiologic and antiarrhythmic activities of 4-amino-N-[2-(diethylamino)ethyl]-3,5-dimethylbenzamide, a sterically hindered procainamide analogue.
abstract: Procainamide is a widely used antiarrhythmic that is fraught with therapeutic limitations such as a short half-life, production of autoimmune antibodies and a lupus-like syndrome, and complex pharmacokinetics. We synthesized the congeners of procainamide possessing one or two methyl substituents ortho to the 4-amino moiety (compounds 4 and 5, respectively), in order to sterically encumber the 4-amino substituent and prevent or diminish the rate of metabolic N-acetylation. Moreover, we anticipated that this structural alteration might eliminate the autoimmune toxicities associated with procainamide. Like procainamide, the two methylated analogues significantly reduced the rate of rise and amplitude of the action potential when studied in isolated canine Purkinje fibers. Whereas procainamide caused no significant change in action potential duration (APD), both methylated congeners significantly reduced APD at 70% and 95% repolarization. Moreover, the dimethylated congener was significantly more efficacious than procainamide in reducing ERP (effective refractory period) and increasing the ERP/APD70. The ability of these compounds to block ouabain-induced arrhythmias was studied in anesthetized dogs. Addition of two methyl groups ortho to the amine produced an increase in potency: The conversion doses for procainamide and the monomethyl and dimethyl congeners were 19.0, 18.3, and 14.3 mg/kg, respectively, following iv administration. After iv administration to rats, procainamide was extensively metabolized to N-acetylprocainamide and displayed a half-life of 0.4 h. In contrast, dimethylprocainamide was not metabolized by N-acetylation, had a half-life of 1.4 h, and provided greater peak plasma concentrations. Thus, addition of methyl substituents ortho to the 4-amino group of procainamide alters the electrophysiological characteristics of the compound, increases its potency against ouabain-induced arrhythmias in vivo, increases its plasma half-life, and prevents N-acetylation.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285.
authors.forename: D W
authors.initials: DW
authors.lastname: Robertson
authors.forename: E E
authors.initials: EE
authors.lastname: Beedle
authors.forename: H
authors.initials: H
authors.lastname: Wilson
authors.forename: C J
authors.initials: CJ
authors.lastname: Parli
authors.forename: J K
authors.initials: JK
authors.lastname: Smallwood
authors.forename: M I
authors.initials: MI
authors.lastname: Steinberg
mesh_terms: D000107:Acetylation; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D004594:Electrophysiology; D006329:Heart Conduction System / Q000502:physiology*; D008297:Male; D011342:Procainamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C056427:4-amino-N-(2-(diethylamino)ethyl)-3,5-dimethylbenzamide; D011342:Procainamide