Future Directions

In order to discover new antiarrhythmic drugs it is important to identify suitable arrhythmia targets, as well as molecular targets. It is also important to realize that both the induction, and maintenance, of arrhythmias is complex, may not be identical, and depends on the interplay of a number of different ion currents. Thus, simple reductionist models for arrhythmias and their treatment that are based upon analogies with diseases such as microbial infection and antibacterial drugs do not work well, since for arrhythmias there is often no one single agent responsible for the induction and/or the maintenance of arrhythmias.

A better disease analogy for arrhythmias might be epilepsy where multiple processes participate in the induction and maintenance of an epileptic attack. Despite this, it is possible to provide prophylaxis against epilepsy with a variety of drugs acting by different mechanisms.

It is important that certain conceptual steps are taken before embarking on an antiarrhythmic drug discovery program. Thus, in any antiarrhythmic drug program it is important to:

1. Clearly identify the target arrhythmia, and its anatomical location. A target arrhythmia should be as homogeneous as possible on the assumption that there is one arrhythmic mechanism responsible for a particular arrhythmia. Arguing by analogy from one type of arrhythmia to another may not be relevant.

2. Identify conditions and mechanisms unique to the target arrhythmia, its induction, and maintenance. Such knowledge provides possible avenues by which specificity of action can be achieved.

3. Choose a specific mechanistic objective for the drug so as to confer selectivity for the target arrhythmia (e.g., special characteristics such as blockade of a particular ion channel, or an arrhythmogen, tissue selectivity, frequency dependence).

4. Identify special factors that might confer therapeutic utility, e.g., special pharmacokinetic factors, or a special pharmacological profile. An example is the use of intravenous adenosine for termination of supraventricular nodal tachycardia. In this case the mechanism of action, and very short duration, confer special attributes that allow this drug to be used, but only against a specific arrhythmia.

5. Explicitly state the approach to be used.

The following section exemplifies the manner in which a new antiarrhythmic, RSD1235, was discovered. In this example the logic, procedures, and serendipitous findings are identified and discussed. An example of an approach to discovering a new antiarrhythmic drug

The RSD1235 program began with an initial goal of discovering an antiarrhythmic drug selective for the fatal arrhythmias induced by acute myocardial infarction during the ischemic phase. This was considered a worthy target despite acknowledged difficulties and previous failure, since ventricular fibrillation is the single largest cause of mortality in Western Europe and North America. In accord with the approaches and criteria discussed above, five factors were considered:

1. The target arrhythmia was ventricular tachycardia and fibrillation caused by acute myocardial infarction in the ischemic phase of myocardial infarction. The ischemic phase is recognized to be when the most lethal of all ventricular arrhythmias occur.

2. The mechanism targeted was chosen on the basis that ischemia produces profound changes in excitability, conduction, and refractoriness that involve Na +, Ca2'+, and K+ ion channels. Such changes directly precipitate in, and maintain, arrhythmias. It was assumed that abolition of the activity of such ion channels would render ischemic tissue quiescent, thereby preventing its participation in arrhythmias. Quiescent cardiac tissue cannot directly participate in arrhythmias, although injury currents might do so.

3. The condition targeted was ischemia since ischemic tissue differs from normal in numerous ways, and it is the site of the initiation and maintenance of arrhythmias. Most importantly it is acidic and has a high potassium concentration.

4. The specific pharmacological target(s) were the ion channels in ischemic tissue so as to prevent their participation in ischemic arrhythmogenesis. The major target channel was that for sodium, although potassium and calcium channels were also considered.

5. The specific approach was to create a blocker of sodium ion channels (plus other ion channels if necessary) that was selectively active in, or activated by, conditions found in ischemic tissue.

Ischemia-induced arrhythmias are most common early (minutes) after the onset of ischemia and are due to disturbed excitability, conduction velocity, and refractoriness resulting in multiple and complex re-entry circuits.43 The antiarrhythmic requirement was for a mixed ion channel blocker, selective for ischemic tissue. In particular sodium channel block would reduce excitability and conduction thereby converting uni- to bidirectional conduction block. At the same time concurrent potassium channel block would increase refractoriness. While such mechanisms operate for conventional class 1 and 3 antiarrhythmics, their lack of ischemic tissue selectivity means that their beneficial effects are outweighed by proarrhythmias. Thus ischemic selectivity was vital.

Attempts have been made to target arrhythmia pathology but the history of targeting drugs for ion channels in normal cardiac tissue is replete with failures. Previous strategies tried to take advantage of the characteristic high rate of arrhythmias by concentrating on frequency dependent drugs, but such drugs have limited efficacy against ischemia-induced arrhythmias. One putative strategy is restoration of the disordered electrophysiology in ischemic tissue. However, this appears to be of limited value since ischemic tissue is doomed to die, unless the tissue is reperfused. Such an approach is feasible if only to keep ischemic tissue alive and functioning normally before reperfusion by surgery or drugs.

A strategy of rendering ischemic tissue electrically quiescent appears counterintuitive until it is recognized that the most lethal phase for ischemic arrhythmias is when the ischemic tissue is still electrically active, and that the occurrence of arrhythmias falls as the tissue becomes electrically quiescent before dying. If this is so, why not hasten and abbreviate the duration of the process of electrical quiescence so as to reduce the chance of arrhythmias? There are potential problems with this approach since there is evidence that sodium channel blockers acting upon ischemic tissue can initiate re-entry arrhythmias.44 This mechanism was probably one of the possible mechanisms for the increased mortality seen in the CAST study.17 However, this potential problem could be lessened by concomitant potassium channel blockade.

It has repeatedly been shown that selective sodium and potassium channel blockers have limited antiarrhythmic efficacy, and all have proarrhythmic activity. Mixed channel blockers may not be that much better although the multichannel blocker amiodarone is an antiarrhythmic drug that unequivocally saves lives.

How can an antiarrhythmic action be made selective for ischemic tissue, or for ischemia-induced arrhythmias? One approach is frequency dependence, as has been discussed previously, while the other takes advantage of the conditions in ischemic tissue. An antiarrhythmic drug activated by ischemic conditions would have ischemia selectivity. A Na+ / K+ channel blocker acting selectively in ischemic tissue, by a combination of increased refractoriness, reduced conduction, and suppression of excitability, would render ischemic tissue quiet and thereby incapable of participating in ischemic arrhythmogenesis. However, since ischemic tissue still has a low membrane potential, it can be a source of injury currents that can act as arrhythmia generators.45 However, ischemic arrhythmias are rare at a time when ischemic tissue is electrically quiet, but still partially polarized.

With this rationale, how can the conditions found in ischemia be utilized to provide selectively? There are examples of drug selectivity being achieved by using tissue-selective enzymes to release active drug from its prodrug. However, there are no known enzymes activated by ischemia that could be used for such a purpose. Another classic approach to site-specific activation is protonation, as with omeprazole which is activated by stomach acid.

Many sodium channel blocking antiarrhythmic drugs are tertiary amines that are active in their charged form within the cell. If a drug acts on the outer surface of the cell in its charged form, then the acidity in ischemic tissue could be used to elevate concentrations of the active species of such a drug.46'47 In an analogous manner elevated extracellular potassium might make channels more vulnerable to some types of ion channel blocking drugs. Elevated K+ also potentiates sodium channel blockers that bind to the inactivated sodium channel. Thus, a compound whose potency for sodium and potassium blockade is increased by raised potassium and hydrogen ion concentrations might have selectivity for ischemic tissue.

Such thinking led to a specific strategic search for such compounds as discussed in Walker and Guppy.48 The following is a summary of a program that required an SAR approach to obtaining ischemia-selective compounds. It was centered on a lead compound with sodium-blocking actions that could potentially be increased by acidity. The choice of lead compound was based upon exploratory work with tetrodotoxin, sparteine analogs, and benzeneacetamide derivatives as well as calcium channel blockers. One of the latter compounds, RSD921, proved structurally suitable as a sodium channel blocker which also blocked the IKur channel.49 However, its actions were not potentiated by acid or raised by extracellular potassium and it did not provide the required antiarrhythmic protection. However, since it was suitable as a pharmacophore a systematic SAR approach was made to obtain better compounds as outlined in Figure 23.

There were four sites on RSD921 that could be systematically studied by chemical substitutions or additions. Thus many changes could be made to A but its size and substituents were not of major importance. The pKa of the nitrogen in the ring at B was very important. The best selectivity for antiarrhythmic activity was seen in those compounds where

The groundwork

Systematic exploration of the pharmacological properties (using various classes of drugs) that confer antiarrhythmic protection in the setting of myocardial ischemia.

Statement of requirements

Ion channel blockade (principally sodium?) potentiated in ischemic conditions (principally pH~6.5)

Potential pharmacophores

I. Benzeneacetamides (opiates) II. Sparteine analogs III. Tetrodotoxin IV. Calcium channel blockers (verapamil - phenylalkylamine)

Choice of pharmacophores

I was chosen based upon the pharmacological profile, ease of chemical manipulation of the molecule, and potentially favorable pharmacokinetics. RSD 921 was the lead compound.

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