Bidisomide (SC-40230) is a class I antiarrhythmic agent. The effects of bidisomide on the electrophysiology of the intact heart were studied using an anesthetized dog model. Three cumulative intravenous doses of bidisomide were studied (n = 5)-1.5, 11.5, and 22.1 mg/kg-given as a loading dose followed by a maintenance infusion to produce three plasma concentration ranges-I .9-2.3, 17.2-21.2, and 22.7-24.1 Fgiml. A placebo group (n = 5) received the equivalent volume of saline. Heart rate, blood pressure, lead II electrocardiogram (ECG) intervals, as well as conduction, refractoriness, and nodal function were measured. Placebo had no effect on any parameter. With the exception of prolonging the atrial refractory period, bidisomide had no effect on any parameter at the lowest dose studied. Bidisomide caused a dose-dependent and statistically significant increase in sinus node recovery time, atrial and ventricular conduction time, atrial effective refractory period, A-H and H-V intervals, P-R and QRS intervals, Wenckebach point, and spontaneous cycle length. The effect of bidisomide on atrial refractory period and on A-H interval was cyclelength dependent. Bidisomide increased or did not change ventricular refractory period in the five dogs studied. Blood pressure decreased less than 15% at plasma bidisomide concentrations up to 20 pg/ml. These experiments demonstrated that bidisomide affects conduction and/or refractoriness in all parts of the heart and has electrophysiologic effects consistent with ventricular and supraventricular antiarrhythmic activity. 0 1992 Wiley-Liss, Inc.

Garthwaite, S., F. Hatley, L. Frederick, J. Ruby, and C. Cook: Effect of SC-40230, A new class I antiarrhythmic agent, on canine ventricular tachycardias. Drug Dev. Res. 17:119-133, 1989. SC-40230, a-[2-[acetyl( 1 -methylethyl)amino]ethyl]-tr-(2-chlorophenyl)-l -piperidinebutanamide, a new class I antiarrhythmic agent, was tested for efficacy against coronary ligation-induced arrhythmias and ouabain toxicity arrhythmias in dogs. Doses of 9 mg/kg i.v. and 15, 25, and 35 mgikg p.0. significantly reduced ectopic rate in conscious dogs that had undergone ligation of the left anterior descending coronary artery 24 hr prior to testing. Plasma concentrations of SC-40230 ranging from 3 to 9 pg/ml corresponded with ectopic rate reductions of 10-82% in the coronary ligation model. was well tolerated at all doses tested in the conscious dogs. A 5 mgikg i.v. dose of SC-40230 converted ouabain-induced ventricular tachycardias to normal sinus rhythm in anesthetized dogs. The antiarrhythmic effect of SC-40230 in the ouabain toxicity model was reversed by large ( 5 240 U) doses of insulin. The experiments described in this study demonstrated that SC-40230 is a well-tolerated new class I antiarrhythmic agent with intravenous and oral effectiveness against ventricular arrhythmias.

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.

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ChemInform Abstract Condensation reaction of the acetonitrile (I) with the chloride (II) gives the nitrile (III) which is transformed into the carboxamide (IV) by hydration and subsequent hydrogenolysis. Acylation of (IV) with the acid chlorides (V) produces the target amides (VI). In contrast, the use of trifluoroacetic anhydride (VII) results in dehydration, forming the nitrile (VIII). The analogues (XI) of disobutamide are prepared by alkylation of (IX) with 1-(chloroacetyl)piperidine (X). The indolizidinones (XV) are synthesized as outlined in the reaction scheme. The disobutamide analogues (VI), (XI), and (XV) and further derivatives, described in the original paper, are evaluated for their antiarrhythmic activity.