Current Medicinal Chemistry - Cardiovascular & Hematological Agents - Volume 1, Issue 3, 2003

Arrhythmias are considered to be an important risk factor, which significantly contributes to mortality and morbidity of cardiovascular patients. However, presently available antiarrhythmic drugs are not generally accepted as a means for risk reduction, mainly due to proarrhythmic side effects intrinsically associated with their mode of action. This was the disappointing result of several clinical studies carried out more than 10 years ago using class I and class III antiarrhythmics. Consequently, antiarrhythmic therapy mainly focussed on electrical device such as the implantable cardioverter defribrillator, where it was believed that no proarrhythmic potential was given. Thus, there was some time left for medicinal chemists to think about failure and possible improvement of existing antiarrhythmics. In addition, they had the opportunity to explore interesting novel antiarrhythmic targets amply provided by new techniques in electrophysiology and molecular biology during the last decade. Of course, the questions “do we really need new antiarrhythmics” and “can they really compete with electrical device” will continuously accompany these efforts. Looking at cost benefit ratios, we think that an effective and safe antiarrhythmic agent has a good chance to compete. In the present issue of Current Medicinal Chemistry - Cardiovascular & Hematological Agents K. Lee starts with a review on existing IKr channel (HERG) blockers, the main representatives of class III agents. In particular, he highlights the efforts to improve the reverse frequency dependence profile of the IKr blockers by optimizing the onset and recovery time constant of the IKr or the balance between the block of IKr and Ca++ channels in the heart to eliminate the proarrhythmic risk. In this context the HERG channel is one of the best-explored ion channel target regarding our structural knowledge of ligand binding. On the other hand for safety reasons it is a prerequisite from the drug administration authorities, that non-cardiovascular drugs are free of a cardiac side effect such as HERG blockade, not taylored for arrhythmias. A. Zolotoy et al. use the knowledge obtained by the intense exploration of HERG blockers to create a model, based on physicochemical determinants, how to avoid this unwanted and dangerous sideeffect. Class III properties, however, are not restricted to IKr blockade alone. A fascinating discovery made by means of detailed patch clamp technique showed that besides IKr another potassium channel, IKs, contributes to repolarization of the cardiac action potential. Could blockers of this channel differ from existing IKr blockers regarding their antiarrhythmic and safety profile? In his contribution, U. Gerlach highlights the efforts and available blockers in this field. A potassium channel that is silent under normal conditions but opens and subsequently shortens the cardiac action potential in myocardial ischemia is the cardiac ATP sensitive potassium channel SUR2A / Kir6.2. Blockers of this channel have no proarrhythmic side effects under normal conditions but are highly effective against ischemically induced arrhythmias. H. Englert et al. review the target, existing blockers and recent efforts to design selective compounds aiming at the prevention of sudden cardiac death. Another, therapeutically attractive target is represented by the voltage-gated potassium channel Kv1.5, which differs from other cardiac potassium channels since it is functional only in the atria. J. Brendel and colleagues focus on this new concept and review blockers of Kv1.5 as a promising new strategy to treat and prevent atrial arrhythmias without the risk of inducing potentially lethal proarrhythmic side effects in the ventricles. We would like to thank all authors for their excellent and timely reviews.

There have been extensive efforts to develop IKr channel blockers as a new antiarrhythmic agent for atrial or ventricular fibrillation, since it was demonstrated that selective blockade of the rapidly activating delayed rectifier K+ channel (IKr) in the heart is not deleterious for the total mortality in fatal ventricular arrhythmia patients. Among them, dofetilide and KCB-328 blocks the IKr specifically. Therefore, it increases the action potential duration (APD) selectively. Ibutilide, trecetilide, nifekalant, dronedarone, BRL-32872, H345 / 52 and ersentilide block the IKr. However, they modify also other cardiac channels or receptors. The frequency dependence of the compounds in prolonging the APD varies from the strong reversed tendency of dofetilide to the relatively neutral profile of KCB-328 and BRL-32872. Every compound reported so far has a proarrhythmic potential of torsade de pointes induction under certain conditions, although depending on the structure, the intensity may be somewhat different. In the coming decade, efforts to improve the reverse frequency dependence profile of the IKr blockers by optimizing the onset and recovery time constant of the HERG block (e.g. KCB-328, vesnarinone) or the balance between the block of IKr and Ca++ channels in the heart (e.g. BRL-32872, H 345 / 52) to eliminate the proarrhythmic potential of the currently known IKr blockers are warranted. Further trials are also needed to discover more favorable compounds with multiple receptors including IKr (e.g. nifekalant, dronedarone) for treating ventricular arrhythmias.

The data on the activities of all previously described HERG blockers and of the most widely cited IKr blockers were analyzed with respect to the effect of potential charged center(s) and its shielding by surrounding structural elements. The following model was considered: the less shielding of the charged form of the drug occurs, the easier its deprotonation will be and the less potency of the blockade of HERG / IKr channels will be. Tertiary amines which form ammonium ions shielded by two structural fragments of the drug molecule were found to be potent HERG / IKr blockers with IC50 < 1 μM (16 of 19 compounds, 84%). However, if the charged center was found at the molecular periphery as such groups as dimethylamino, N-methylpiperidino, N-methylpiperazino, N-methylpyrrolidino, pyrrolidino, imidazolo and partial periphery (diethylamino), then only moderate potency for HERG blockade with 1 μM 10 μM) were found to be primary or secondary amines, or neutral or very weakly basic compounds. Ions of primary and secondary amines are susceptible to the fast deprotonation of the charged center and they, as well as non-charged compounds, have a low probability of induction of Torsades de Pointes (TdP). Conformational analysis and modeling of the interaction of the charged fragment of the drugs with acetone, a system that mimics a ketone fragment of HERG / IKr channel, supports preference of the conformation with the shielded charged center for potent HERG / IKr blockers. The absence of stereospecificity of HERG / IKr blockade observed in most of the published studies reinforces the importance of charged center shielding as a key parameter. We suggest that the introduction of a hydroxy group at position 3 relative to a tertiary ammonium charged center, or the introduction of hydroxy, alkoxy or amino groups at position 2 relative to the nitrogen center of an aromatic system, should provide easy access of a water molecule to the proton, thereby facilitating deprotonation and thus leading to a moderate or weak HERG / IKr blockade and a reduced risk of TdP.

Prolongation of the cardiac action potential and the effective refractory period is a proven principle to prevent cardiac arrhythmias, especially under conditions when the action potential is shortened. Several approaches have been made to achieve this effect selectively and without proarrhythmic side effects. Besides the blockade of the cardiac sodium channel, blockade of the delayed rectifier potassium channel IK was attempted to achieve this goal. After the discovery that the delayed rectifier potassium channel IK consists of two distinct channels, the rapidly and the slowly delayed rectifier potassium channel IKr and IKs respectively, blockers for these targets were looked for. But most of the described blockers of IK, like dofetilide and D-sotalol, are highly selective and potent IKr channel blockers or have only a side-activity on the IKs channel, as described for azimilide. These compounds have shown their efficacy in terminating atrial or ventricular fibrillation under certain circumstances, but they also have shown high risk to induce arrhythmias by themselves. It was speculated that IKs channel blockers may be free of this unwanted effect and several companies put effort to find compounds selective for this novel target. The strategies to find potent and selective IKs channel will be reviewed as well as their first results in in-vitro and in-vivo models of arrhythmia. As side effects are a potential danger for this ubiquitous channel, also the safety studies with these compounds will be summarized.

The cardiac ATP sensitive potassium channel (KATP channel) SUR2A / Kir6.2 is an emerging target for antiarrhythmic intervention. This channel accounts for known electrophysiological derangements soon after the onset of myocardial ischemia. Consequently, blockers of this channel have the potential to prevent ischemic malignant arrhythmias and sudden cardiac death in humans. Since cardiac KATP channels are closed at physiological intracellular ATP concentrations (ATPi) and open only when ATPi falls below a critical value, these agents do not affect the normal cardiac action potential and should be devoid of proarrhythmic side effects. Due to the existence of isoforms of this channel, mainly in vascular smooth muscle cells, pancreatic - szlig;-cells and cardiac mitochondria, only specific blockers of SUR2A / Kir6.2 will offer a reasonable option for the treatment of cardiovascular patients at risk of sudden cardiac death. Presently known KATP blockers are derived from diverse classes of compounds with antidiabetic sulfonylureas being their most prominent members. Retrospective evaluations of clinical studies with the sulfonylurea glibenclamide in diabetics revealed antifibrillatory activity to be an important additional effect of this class of compounds. However, for the safe treatment of arrhythmias nearly all presently known blockers lack sufficient selectivity, either within the target family or with respect to other ion channels modulating the cardiac action potential. The present article illustrates the new principle in terms of molecular biology and electrophysiology and summarizes all presently known KATP blockers. As a highlight, first strategies to come to selective SUR2A / Kir6.2 blockers, such as HMR 1883, are reviewed.

Atrial arrhythmias are a common problem in cardiological practice. Despite the availability of several antiarrhythmic drugs, there is a medical need for safer and more efficient antiarrhythmic treatment. Compounds that act atrial selectively without prolonging the QTc-time and without negative inotropy to terminate and / or prevent atrial arrhythmias would be of high interest. In this context, the voltage-gated potassium channel Kv1.5 is regarded as a promising target to achieve atrial selectivity, which in turn would be associated with fewer side effects than classical antiarrhythmics. This review summarizes patents and other publications on compounds which show this novel mode of action. The chemistry, selectivity and structure-activity data disclosed in the literature are discussed in light of recent work demonstrating the antiarrhythmic efficacy of Kv1.5 blockers in vivo. Several studies in pig, dog or goat models have confirmed their proposed atrial selective antiarrhythmic effect in vivo. Most of the more intensively characterized Kv1.5 blockers have turned out not to be selective but also block other ion channels. Based on the currently available data it seems that additional inhibition of Kv4.3 and KACh is beneficial for the desired antiarrhythmic effect or at least does not hamper the atrial selectivity of a Kv1.5 blocker. Significant block of IK1, HERG or sodium channels, however, clearly leads to loss of atrial selectivity and increases the risk of lethal ventricular proarrhythmia.