D- -sotalol

Blockers are antiarrhythmics of class II according to the Vaughan-Williams classification, effective in the treatment of both supraventricular and ventricular tachyarrhythmias. These drugs can also reduce ectopic beats, especially if they are a result of sympathetic activity. Sotalol is a racemic mixture of the -blocking L-isomer and the class III antiarrhythmic D-isomer. This racemic mixture as well as D-sotalol are used as class Ill-antiarrhythmic. 

Figure 20 Synthesis of chiral synthon for D-(+)-sotalol, antiarrhythmic agent stereoselective microbial reduction of N-(4-(2-chloroacetyl)phenyl)methanesulfonamide (65).

These models have been used to study the mechanisms of arrhythmogenesis [43, 44] and to study the actions of drugs such as d-sotalol on propagation [43]. 

Salazar, D., Much, D., Nichola, P., Seibold, J., Shindler, D., and Slugg, P., A pharmacokinetic-pharmacodynamic model of d-sotalol Q-Tc prolongation during intravenous administration to healthy subjects, Journal of Clinical Pharmacology, Vol. 37, No. 9, 1997, pp. 799-809. 

Vos MA, Verduyn SC, Gorgels APM et al. (1995) Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d-sotalol and pacing in... 

Lehmann MH, Hardy S, Archibald D, Quart B, MacNeil DJ. Sex difference in risk of torsade de pointes with d,/-sotalol. Circulation 1996 94 2535—41. 

Pratt CM, Camm AJ, Cooper W, Friedman PL, MacNeil DJ, Moulton KM et al. Mortality in the Survival With ORal D-sotalol (SWORD) trial Wliy did patients die Am J Cardiol 1998 81 869-76. 

The most common mechanism of dysrhythmias at the molecular level is by inhibition of the potassium channels known as IK, which are encoded by the human ether-a-go-go-related gene (HERG). The antidysrhythmic drugs that affect these channels include almokalant, amiodar-one, azimilide, bretylium, dofetilide, ibutilide, sematilide, D-sotalol, and tedisamil (all drugs with Class III actions) and bepridil, disopyramide, prenylamine, procainamide, propafenone, quinidine, and terodiline (all drugs with Qass I actions). Other drugs that affect these channels but are not used to treat cardiac dysrhythmias include astemizole and terfenadine (antihistamines), cisapride, erythromycin, haloperidol, sertindole, and thioridazine. 

Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, Pitt B, Pratt CM, Schwartz PJ, Veltri EP. Effect of d-sotalol on mortality m patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996 348(9019) 7-12. Erratum in Lancet 1996 348(9024) 416. 

Montero M, Schmitt C. Recording of transmembrane action potentials in chronic ischemic heart disease and dilated cardiomyopathy and the effects of the new class III antiarrhythmic agents D-sotalol and dofetilide. J Cardiovasc Pharmacol 1996 27(4) 571-7. 

A trial of the efficacy of D-sotalol in patients with left ventricular dysfunction (8) was discontinued early when an interim analysis of 2762 patients showed an overall mortality of 3.9% in the D-sotalol group, compared with 2% in the placebo group (9). 

Yasuda SU, Barbey JT, Funck-Brentano C, WeUstem A, Woosley RL. d-Sotalol reduces heart rate hr vivo through a beta-adrenergic receptor-independent mechatrism. Chn Pharmacol Ther 1993 53(4) 436-42. 

Despite the discouraging results of the CAST, post-MI patients with complex ventricular ectopy remain at risk for death. Other drugs besides type Ic drugs have been studied, including sotalol. Sotalol is marketed as a racemic mixture of a D- and L-isomer both are type in potassium blockers, but the L-isomer has /3-blocking actions. Chronic therapy with D-sotalol was studied in patients with remote MI complicated by complex ectopy in the Survival With Oral D-Sotalol (SWORD) trial. Unlike in the CAST, D-sotalol treatment was not designed to cause PVC suppression, yet (as in the CAST) the trial was halted prematurely because of excessive mortality in the treatment arm. Again, the presumed reason for this observation was D-sotalol-related pro arrhythmia. Currently, only two antiarrhythmic... 

Waldo AL, Camm AJ, deRuyter H, et al. Effect of D-sotalol on mortality in patients with left ventricular dysfunction and remote myocardial infarction. Lancet 1996 348 7-12. 

Advani, S.V. Singh, B.N. Pharmacodynamic, pharmacokinetic and antiar-rhythmic properties of d-sotalol, the dextro-isomer of sotalol. Drugs 1995,49, 664 19. 

Waldo, A.L. Camm, A.J. de Ruyter, H. Friedman, P.L. MacNiell, D.J. Pauls, J.F. Pitt, B. Pratt, C.M. Schwartz, P.J. Veltri, E.P. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 1996, 348, 7-12. 

Quinidine, disopyramide, procainamide Amiodarone, dofetilide, D-sotalol, dibutilide Bepridil, terodiline... 

Wells Q, Hardin B, Raj SR, Darbar D. Sotalol-induced torsades de pointes precipitated during treatment with oseltamivir for HlNl influenza. Heart Rhythm 2010 7 (10) 1454-7. 

Similar to CAST, the SWORD (Survival With Oral d-Sotalol) trial investigated whether an antiarrhythmic drug affected mortality. SWORD used d-sotalol, a class III antiarrhythmic drug without substantial beta blocking... 

At this point, it is worth introducing stereoisomers. These are isomeric molecules that have the same molecular formula and hence the same sequence of bonded atoms. However, they differ in the three-dimensional orientation of their constituent atoms. For example, consider the example of the antiarrhythmic drug sotalol. Both d-sotalol and I-sotalol isomers affect 4, that influences cardiac repolarization, but only the I-isomer has beta-blocking effect. Another example is warfarin. The S-isomer is three to five times more potent than the R-isomer, and they are metabolized by different cytochrome pathways, an influence that contributes to variable response and toxicity between batches of the drug and ethnic populations. 

In 1997, chemists from the Process Exploration Labs at Bristol-Myers Squibb Company reported their development of a simple asymmetric synthesis of d-sotalol 105, a Class III antiarrythmia compound, utilising a CBS reduction as the key step (Scheme 14.34). ° Previous efforts towards synthesis of d-sotalol had utilised techniques such as mandelic acid resolution, chiral chromatography and use of chiral homogeneous hydrogenation. The synthesis of d-sotalol via a CBS reduction is of interest as the molecule contains a methanesulfonamide NH proton, which clearly does not interfere with the yield or enantioselectivity of the process despite the acidic nature of this substituent. The authors discuss the various elements of the reduction process that they investigated and conclude that the optimal procedure involves addition of 1 M BH3 THE over a few minutes to a mixture of the (5 )-2-MeCBS catalyst and substrate ketone 102 in MTBE held at room temperature. Under these reaction conditions (on a 1.8 mmol scale), alcohol 103 was obtained in 92% yield with 96% ee. In this instance, the enantiomeric excess was calculated by conversion of the alcohol product to... 

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