J. Med. Chem. 1992,35,705-716
705
Class I11 Antiarrhythmic Activity of Novel Substituted 44(Methylsulfonyl)amino]benzamides and Sulfonamides John W. Ellingboe,**+Walter Spine&* Michael W. Winkley) Thomas T. Nguyen,? Roderick W. Parsons,i Issam F. Moubarak,t Jan M. Kitzen," Donna Von Engen,l and Jehan F. Baglit Division of Exploratory Chemistry and Division of Cardiovascular and Metabolic Disorders, Wyeth-Ayerst Research, C N 8000, Princeton, New Jersey 08543-8000, Division of Chemical Development, Wyeth-Ayerst Research, 64 Maple Street, Rouses Point, New York 12979, and Department of Chemistry, Princeton University, Princeton, New Jersey 08540. Received August 5, 1991
The synthesis and Claw Ill antiarrhythmic activity of a seriea of 4[(methylsulfonyl)amino]be&des and sulfonamides are described. Selected compounds show a potent Class I11 activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having this heterocycle (5, WAY-123,398) was selected for further characterization. Compound 5 was shown to have good oral bioavailability and a favorable hemodynamic profde to produce a 3-fold increase of the ventricular fibrillation threshold and to terminate ventricular fibrillation, restoring sinus rhythm in anesthetized dogs. Voltage-clamp studies in isolated myocytes show that 5 is a potent and specificblocker of the delayed d e r potassium current (ZK) at concentrations that caw significant prolongation of action potential duration.
Sudden cardiac death (SCD) is a leading cause of mortality in Western society. Ventricular arrhythmias are thought to play a major role in SCD,l thus the prevention and control of life-threatening ventricular tachycardias/ ventricular fibrillation has a great therapeutic significance. The majority of these arrhythmias occur in patients suffering from ischemic heart disease or congestive heart failure.2 Clinical evidence and many studies in animal models have also indicated that most life-threatening arrhythmias in these patiente are due to reentry? Currently, the most widely prescribed drugs are those that slow conduction and increase refractoriness by blocking the fast sodium channel. Although these Class I antiarrhythmic agents (Vaughan Williams Classifi~ation~) are very effective in reducing the frequency of premature ventricular contraction, they are not very effective in controlling or preventing life-threatening ventricular arrhythmias. Furthermore, the therapeutic usefulness of Class I agents is severely limited by adverse side effects, the most important of which are the negative inotropic and proarrhythmic effects! Excessive depression of conduction may actually promote reentry and result in proarrhythmic effects. S i l y , a significant block of the fast inward Na current has been shown to decrease myocardial contractility. Both of these effects are thought to be exacerbated in the diseased myocardium. The results of the Cardiac Arrhythmia Suppression Trial (CAST) have clearly shown that potential negative side effects of potent Class I agents can outweigh their clinical benefihs One therapeutic alternative of current interest is the development of agents that prolong refractoriness (Class 111antiarrhythmic effect) without depressing conduction of the cardiac impulse (Class I antiarrhythmic effect). Such an agent should be effective in reentrant arrhythmias: a large and selective prolongation of refractoriness would cause the reentrant impulse to enter tissue that has not yet recovered excitability and thus terminate the arrhythmia. An agent with this pharmacological profile should be devoid of both proarrhythmic effects resulting from excessive depression of conduction and negative inotzopism resulting from the blockade of sodium channels. F'urthermore, agents prolonging the action potential might cause a limited positive inotropic effect, which could be t Division
beneficial in the treatment of arrhythmias in congestive heart failure.' A number of Class 111antiarrhythmics have been disclosed recently. These include sotaloP (l),which also has &blocking activity, E-403l9 (21, UK-68,7981°(3), (1) Olehausen, K. V.; Witt, T.; Pop, T.; Treese, N.; Bethge, K.;
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of Exploratory Chemistry.
8 Division of Cardiovascular and Metabolic Disorders. 8 Division of Chemical Development.
Present address: Rhone-Poulenc Rorer Central Research, Department of Cardiovascular Biology, King of Prussia, PA 19406. Princeton University.
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Meyer, J. Sudden Cardiac Death While Wearing a Holter Monitor. Am. J. Cardiol. 1991,67,381-386. (a) Packer, M. Sudden Unexplained Death in Patients with Congestive Heart Failure: A Second Frontier. Circulation 1987, 72,681-685. (b) Bigger, J. T.; Fleise, J. L.; Kleiger, R.; Miller, J. P.; Rolnitzky, L. M.; and the Multicenter PosbInfarction Research Group. The Relationship among Ventricular Arrhythmias, Left Ventricular Disfunction, and Mortality in the 2 Years after Myocardial Infarction. Circulation 1984,69, 250-258. (a) Rosen, M. R.;Janse, M. J.; Myerburg, R. J. Arrhythmias Induced by Coronary Artery Occlusion: What Are the Electrophysiological Mechanisms? In Life-Threatening Arrhythmias During Ischemia and Infarction; Hearse, D., Manning, A., Janse, M., E&.; Raven Press: New York, 1987;pp 11-47. (b) Frame, L. H.; Bernstein, R. C. Reentry in Clinical Arrhythmias. In Cardiac Electrophysiolgy: A Textbook; Rosan, M. R., Janse, M. J., Wit, A. L., Eds., Futura Publishing Co.: Mount Kisko, NY, 1990; pp 645-670. Vaughan Williams, E. M. A Classification of Antiarrhythmic Actions Reassessed After a Decade of New Drugs. J. Clin. Pharmacol. 1984,24, 129-147. Wooeley, R.L. Antiarrhythmic Drugs. Annu. Rev. Pharmacol. Toricol. 1991,31,427-455. Echt, D. S.; Liebson, P. R.; Mitchell, L. B.; Peters, R. W.; Obias-Manno, D.; Barker, A. H.; Areneberg, D.; Baker, A.; Friedmaa,L.; Greene, H. L.; Huther, M. L.; Richardson, D. W.; and the CAST Investigators. Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo. The Cardiac Arrhythmia Suppression Trial. N . Engl. J. Med. 1991, 324,781-788. Kaumann, A.; Blinks, J. R.Stimulant and Depreasant Effects of Beta-Adrenoreceptor Blocking Agents on Isolated Heart Muscle. Naunyn.-Schmiedeberg's Arch. Phurmacol. 1980,311, 205-218. (a) Singh, B. N.; Vaughan Williams, E. M. A Third Claw of Antiarrhythmic Action. Effects on Atrial and Ventricular Intracellular Potentials, and Other Pharmacological Actions on Cardiac Muscle, of MJ 1999 and AH 3474. Br. J. Pharmacol. 1970, 39, 675-687. (b) Antonaccio, M. J.; Gomoll, A. Pharmacology, Pharmacodynamics and Pharmacokinetice of Sod o l . Am. J. Cardiol. 1990,65, 12A-21A. Oinuma, H.; Miyake, K.; Yamanaka, M.; Nomoto, K.;Katoh, H.; Sawada, K.;Shino, M.; Hamano, S. 4'-[(4-Piperidyl)carbonyl]methanesulfonanilide~as Potent, Selective, Bioavailable Class I11 Antiarrhythmic Agents. J. Med. Chem. 1990, 33,903-905. Cross, P. E.; Arrowsmith, J. E.; Thomas, G. N.; Gwilt, M.; Burges, R.A.; Higgins, A. J. Selective Class III Antiarrhythmic Agents. 1. Bis(arylalky1)amines. J. Med. Cham. 1990, 33, 1151-1155.
OO22-2623/92j 1835-0705$03.00/0 0 1992 American Chemical Society
Ellingboe et al.
706 Journal of Medicinal Chemistry, 1992, Vol. 35,No. 4 Scheme I
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