Current Medicinal Chemistry - Volume 11, Issue 1, 2004

Cardiac arrhythmias represent a major area of cardivascular disease research. Of the possible medical treatments of arrhythmias, drug therapy has gained great importance. In spite of the significant progress achieved in the basic understanding of the electrophysiology and molecular biology of transmembrane ion channels and transporters underlying the mechanism of cardiac arrhythmias and possible drug actions, during the last decade no breakthrough has occurred in the therapy. On the contrary, based on multicentric clinical trials, it is now evident that serious side effects may considerably limit the use of currently available antiarrhythmic agents to abolish or prevent atrial fibrillation and life threatening ventricular tachycardias. Therefore, it seems worthwhile to review some of the possible mechanisms which could taken into account in future drug development strategies. In this ‘Hot topic’ issue, there are included five papers by experts of the field, in which some new aspects, and opinions regarding the possible mechanisms of new drugs under and future developments are described. The first article by Andras Varro et al. summarizes in general the basic electrophysiology of the transmembrane ion channels and possible consequences of their modulation. The paper of Juan Tamargo et al. focuses on various aspects of current and future drug therapy of atrial fibrillation. Joseph Salata et al. and Péter Nánási et al. in their overviews express partly different opinions regarding the future perspectives of the inhibition of the slow delayed rectifier outward potassium current (IKs) as a possible antiarrhythmic strategy. In the last paper, Peter Mátyus et al. present the medicinal chemistry of a new series of compounds with a dual mode of action designed and developed at their own labs. supporting the concept that a finely tuned blockade of carefully selected ion channels may result in a therapeutically particularly valuable profile. We do hope that all papers per se, and the issue in its entirety, will give the reader some hints to understand the complexity of antiarrhythmic drug therapy, and will initiate further research in this area.

One possible mechanism of action of the available K-channel blocking agents used to treat arrhythmias is to selectively inhibit the HERG + MIRP channels, which carry the rapid delayed rectifier outward potassium current (IKr). These antiarrhythmics, like sotalol, dofetilide and ibutilide, have been classified as Class III antiarrhythmics. However, in addition to their beneficial effect, they substantially lengthen ventricular repolarization in a reverse-rate dependent manner. This latter effect, in certain situations, can result in life-threatening polymorphic ventricular tachycardia (torsades de pointes). Selective blockers (chromanol 293B, HMR-1556, L-735,821) of the KvLQT1 + minK channel, which carriy the slow delayed rectifier potassium current (IKs), were also considered to treat arrhythmias, including atrial fibrillation (AF). However, IKs activates slowly and at a more positive voltage than the plateau of the action potential, therefore it remains uncertain how inhibition of this current would result in a therapeutically meaningful repolarization lengthening. The transient outward potassium current (Ito), which flows through the Kv 4.3 and Kv 4.2 channels, is relatively large in the atrial cells, which suggests that inhibition of this current may cause substantial prolongation of repolarization predominantly in the atria. Although it was reported that some antiarrhythmic drugs (quinidine, disopyramide, flecainide, propafenone, tedisamil) inhibit Ito, no specific blockers for Ito are currently available. Similarly, no specific inhibitors for the Kir 2.1, 2.2, 2.3 channels, which carry the inward rectifier potassium current (Ik1), have been developed making difficult to judge the possible beneficial effects of such drugs in both ventricular arrhythmias and AF. Recently, a specific potassium channel (Kv 1.5 channel) has been described in human atrium, which carries the ultrarapid, delayed rectifier potassium current (IKur). The presence of this current has not been observed in the ventricular muscle, which raises the possibility that by specific inhibition of this channel, atrial repolarization can be lengthened without similar effect in the ventricle. Therefore, AF could be terminated and torsades de pointes arrhythmia avoided. Several compounds were reported to inhibit IKur (flecainide, tedisamil, perhexiline, quinidine, ambasilide, AVE 0118), but none of them can be considered as specific for Kv 1.5 channels. Similarly to Kv 1.5 channels, acetylcholine activated potassium channels carry repolarizing current (IKAch) in the atria and not in the ventricle during normal vagal tone and after parasympathetic activation. Specific blockers of IKAch can, therefore, also be a possible candidate to treat AF without imposing proarrhythmic risk on the ventricle. At present several compounds (amiodarone, dronedarone, aprindine, pirmenol, SD 3212) were shown to inhibit IKAch, but none of them proved to be selective. Further research is needed to develop specific K-channel blockers, such as IKur and IKAch inhibitors, and to establish their possible therapeutic value.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with substantial cardiovascular morbidity and mortality. The arrhythmia can be initiated and / or maintained by rapidly firing foci, single- and multiple-circuit reentry. Once initiated, AF alters atrial electrical and structural properties (atrial remodeling) in a way that promotes its own maintenance and recurrence and may alter the response to antiarrhythmic drugs. Thus, initial episodes of paroxysmal (self-terminating) AF lengthens to the point where the arrhythmia becomes persistent (requires cardioversion to restore sinus rhythm) and permanent. AF usually requires a trigger for initiation and a favorable electrophysiological and / or anatomical substrate for maintenance. The substrate includes both cardiovascular (coronary artery disease, valvular heart disease, heart failure, hypertension, dilated cardiomyopathy) and non cardiovascular diseases (thyrotoxicosis, pulmonary diseases). Accordingly, the initial step in patients with AF requires a careful assessment of symptoms and identification of underlying reversible triggers and potentially modifiable underlying structural substrate and treat them aggressively.. In contrast to other cardiac arrhythmias, antiarrhythmic drugs (ADs) are the mainstay of therapy. Long-term treatment of AF is directed to restore and maintain the sinus rhythm with class I and III ADs (rhythm-control) or to allow AF to persist and ensure that the ventricular rate is controlled (rate-control) with atrioventricular nodal blocking drugs (digoxin, β-blockers, verapamil, diltiazem) and prevent thromboembolic complications with anticoagulants. However, the long-term efficacy of ADs for preventing AF recurrence is far from ideal, because of limited efficacy (AF recurs in at least one-half of the patients) and potential side effects, particularly proarrhythmia. Thus, the choice of the appropriate AD will depend on the temporal pattern of the arrhythmia, the presence of associated diseases, easy of administration and adverse effects profile, particularly the risk of proarrhythmia. The recent finding that angiotensin converting enzyme inhibitors and β-blockers reduce the incidence of AF in patients post myocardial infarction with left ventricular dysfunction confirmed the importance of targeting the underlying arrhythmogenic substrate. This review focuses on the mechanisms underlying AF and the mechanism of action and the efficacy and safety profile of the ADs used in the treatment of atrial fibrillation. The advantages and disadvantages of rhythm and rate control, the role pill in a pocket concept and the role of the new ADs are dicussed.

The slowly (IKs) and rapidly (IKr) activating delayed rectifier K+ currents play important roles in cardiac ventricular repolarization. Compared with IKr, however, IKs has important distinguishing characteristics, including ß-adrenergic receptor stimulation and accumulation at rapid rates that may impart significant therapeutic relevance. Therefore, development of selective IKs inhibitors has been pursued as a strategy for providing potentially safer and more effective Class III antiarrhythmic agents and pharmacological tools for elucidating the normal physiological and potential pathological role of IKs in cardiac repolarization. We have identified a series of 3-Acylamino-1,4 benzodiazepines that are very potent and selective inhibitors of IKs. A representative compound, L-768,673 (1) (IC50∼8nM), has been extensively characterized for its pharmacologic activity. L-768,673 concentration-dependently prolongs action potential duration in a frequency-independent manner in vitro, but decreases transmural dispersion of refractoriness, a risk factor for arrhythmia induction. In conscious dogs, L-768,673 administered IV (0.3-100 μg / kg) and PO (0.03-1 mg / kg) elicits consistent but limited (5-15%) QTc prolongation, and increases ventricular refractory period more at fast than at slow pacing rates, indicating a “forward” rate-dependence in vivo. In an anesthetized canine model of anterior myocardial infarction, IKs blockers suppress the development of ischemic ventricular fibrillation at intravenous doses that minimally prolong the QT interval. IKs blockers display an interesting and intriguing profile of effects on cardiac electrophysiologic parameters that differ in remarkable ways from other selective Class III agents such as IKr blockers. It remains to be determined if these properties can be exploited clinically to provide more effective and safer treatment of cardiac arrhythmias.

The goal of this paper is two fold. First, we attempt to review the reports available on the role of IKs in myocardial repolarization. Based on theoretical considerations and experimental results, it seems reasonable to assume that IKs blockade will lengthen the action potential. However, results obtained with IKs blockers, like chromanol 293B or L-735,821, are conflicting, since from slight lengthening to marked prolongation of action potentials were equally obtained. Although these contradictory results were explained by interspecies or regional differences, the role of IKs in repolarization is a matter of growing dispute. In the second part of this study, we simulated the performance of IKs during cardiac action potentials. We compared the profile of the predicted current in three mathematical models in order to determine the relative role of the current in repolarization. We studied the effect of the cycle length, action potential duration and height of the plateau on the profile of IKs in epicardiac, endocardiac and midmyocardiac ventricular action potentials. The results indicate that the height of the plateau is the most important parameter to control activation of IKs in cardiac tissues, and accordingly, the interspecies and regional differences observed in the efficacy of IKs blockers are likely due to the known differences in action potential morphology. We conclude also that IKs blockade may have unpredictable effects on the length of the action potential in a diseased heart, questioning the possible therapeutic value of drugs blocking IKs.

Cardiac arrhythmias represent a major area of cardiovascular research, and for drug therapy, a large choice of antiarrhythmic agents have been available. However, clinical trials with antiarrhythmic drugs have recently indicated that serious side effects may considerably limit the use of various antiarrhythmic agents, in particular, for preventing arrhythmia-related mortality. Amiodarone with its complex mode of action, while exerting a strong and favorable antiarrhythmic action, posseses extracardiac untoward side effects originating from its chemical structure. In this paper, we report on our attempt to develop conceptually new, therapeutically valuable antiarrhythmic compounds, in which Class I / B and Class III features were combined into single molecules bearing no structural resemblance to amiodarone. Synthesis and pharmacological screening of series of N-(phenylalkyl)-N- (phenoxyalkyl)amines led us to discover some new promising compounds with the required dual mode of action. GYKI-16638, selected for further investigation, was also found to possess a remarkable in vivo antiarrhythmic effect, and it is now considered as a safe new antiarrhythmic drug candidate.

A major goal in contemporary drug design is to develop new ligands with high affinity of binding toward a given protein receptor. Pharmacophore, which is the three-dimensional arrangement of essential features that enable a molecule to exert a particular biological effect, is a very useful model for achieving this goal. If the three-dimensional structure of the receptor is known, pharmacophore is a complementary tool to standard techniques, such as docking. However, frequently the structure of the receptor protein is unknown and only a set of ligands together with their measured binding affinities towards the receptor is available. In such a case, a pharmacophore-based strategy is one of the few applicable tools. Here we present a broad, yet concise guide to pharmacophore identification and review a sample of applications for drug design. In particular, we present the framework of the algorithms, classify their modules and point out their advantages and challenges.

This article reviews the docking field starting from basic docking algorithms and describing the latest advances. We present the algorithmic framework and classify the state of-the-art methods. We point out the bottlenecks of the methods, like flexibility, absence of absolute scoring functions and explain what types of information can potentially be added to improve the results.