A key role has been established for platelet activation and thrombus formation in the pathogenesis of acute coronary syndromes, and restenosis after percutaneous interventions. Antiplatelet agents that have a wider spectrum of activity than aspirin, and clopidogrel would be expected to provide improved antithrombotic protection. Preclinical studies were used to predict clinical efficacy of orally active GPIIb/IIIa antagonists such as xemilofiban, sibrafiban, lefradafiban, and orbofiban. While clinical trials have shown potent and sustained platelet inhibition, outcomes of trials with these first generation GPIIb/IIIa compounds have been disappointing. The active moiety of orbofiban is a potent and specific inhibitor of fibrinogen binding to GPIIb/IIIa, leading to inhibition of platelet aggregation to a wide variety of agonists. Studies comparing inhibition of aggregation and bleeding suggest that chronic inhibition of platelet aggregation can be achieved without major bleeding side effects. Thrombus formation is prevented in canine models of thrombosis. Orbofiban is approximately 28% bioavailable with a t(1/2) of 18 hr. The high bioavailability, long half-life, and potential safety suggest orbofiban would be suitable for chronic oral administration. Clinical data demonstrate that orally administered orbofiban has the desired pharmacodynamic effect of inhibiting platelet aggregation but does not demonstrate clinical benefit when examined in large-scale trials.

SCa has dose-dependent antithrombotic efficacy and inhibits ex vivo platelet aggregation. ASA, heparin, or saline was ineffective in this model. SCa (0.5X) plus ASA and heparin maximized the antithrombotic effect of this lower dose of SCa.

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.

The cardiac and general haemodynamic effects of SC-40230, a newly developed anti-arrhythmic agent with both class 1a and 1b properties, were assessed in two different types of experiments using anaesthetised dogs, and in experiments using isolated cat papillary muscles. At the canine anti-arrhythmic dose (9 mg.kg-1 intravenously), SC-40230 decreased the maximum rate of rise of the left ventricular pressure (LV dP/dtmax) by 20%. It decreased heart rate slightly, and lowered (greater than 10%) blood pressure only at doses greater than the canine anti-arrhythmic dose. In these experiments there were dose dependent increases in the P-R interval and the QRS duration. In isolated cat papillary muscles, SC-40230 had a weak negative inotropic effect (IC20 = 3.3 X 10(-5) mol.litre-1) which was less than that previously reported for disopyramide phosphate (IC20 = 1.8 X 10(-5) mol.litre-1) or mexiletine (IC20 = 2.1 X 10(-5) mol.litre-1). These findings suggest SC-40230 has a minimal cardiovascular and haemodynamic side effect potential in its anti-arrhythmic dose range. If these results are confirmed in clinical studies, SC-40230 may have an improved side effect profile versus other anti-arrhythmic drugs such as disopyramide.

A series of 4,4-disubstituted tetrahydro- and 4,4-disubstituted hexahydro-3H-pyrido[1,2-c]pyrimidin-3-ones (4 and 5, respectively) were prepared from 2-aryl-2-(2-piperidinyl)-4-[N,N-bis (1-methylethyl)amino] butanamides (2). Individual racemates of the piperidinyl amides 2 were converted to pure racemic diaza bicyclic compounds that were evaluated for antiarrhythmic activity in the Harris dog model and anticholinergic activity in a muscarinic receptor binding assay. Selected compounds were subsequently evaluated for hemodynamic effects in anesthetized dogs where blood pressure depression and negative inotropic activity were assessed. Of this group, 4a (R = CH3) and 5a (R = CH3) showed the most favorable pharmacological profiles; the former compound was chosen for toxicity testing over the latter due to its lack of noncompetitive inhibition of acetylcholine-induced contractions of guinea pig ileum segments. Clinical evaluation is now under way.

No abstract