Article

Recent Advances in the Development of Selective Anti-Atrial Fibrillation Drugs

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DOI:https://doi.org/10.15420/apc.2007:1:1:52

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Atrial fibrillation (AF) is the most common cardiac arrhythmia and the occurrence of AF increases with age. The prevalence of AF rises from 0.5% in people in their 50s to 5% in people over the age of 65 years. This rises to nearly 10% in the octogenarian population.1 AF is a major cause of morbidity and mortality, increasing the risk of death, congestive heart failure (CHF) and embolic phenomena, including stroke.1 It is believed that AF is a lifetime risk in the ageing population2 and it is emerging as a major public health concern.3 The management of AF includes surgery, ablation4,5 and pharmacological therapies.6 However, only some cases are amenable to surgical or ablative therapies, and most of them require antiarrhythmic drug treatment.6 Over the years, delayed rectifier K+ currents (IK), especially the rapidly-activating IK (IKr, encoded by hERG, ether-a-go-go gene), have been important targets for antiarrhythmic drugs. Blockade of these ion channels (class III antiarrhythmic drugs) leads to a prolongation of atrial and ventricular action potential duration (APD) and the refractory period, which is the desired antiarrhythmic effect.7,8 However, prolongation of ventricular repolarisation causes a prolongation of the QT interval and an increased propensity for life-threatening ventricular arrhythmias.9 Therefore, there is a clear need to develop new drugs that may act mainly on electrical activity in the atrium of the human heart to prevent or treat AF.

Ion Channel Currents in the Atrium and Ventricle of the Human Heart

It is well-known that human cardiac APD and the refractory period generally depend on the balance of inward and outward currents in atrial and ventricular myocytes (see Figure 1). Inward currents include the Na+ current (INa) and L-type Ca2+ current (ICa.L), and outward currents include the transient outward K+ current (Ito), IKr and slowly-activating delayed rectifier K+ current (IKs) and inward rectifier K+ current (IK1). In general, INa channel activation depolarises cell membrane and initiates action potential (phase 0), then Ito activation forms a fast repolarisation (phase 1). Activation of ICa.L maintains the plateau of the action potential (phase 2); IKr and IKs gradually activate and induce slow repolarisation during phase 2. Finally, activation of IK1 channels induces final repolarisation (phase 3) and maintains resting membrane potential (phase 4). The electrogenic Na+–Ca2+ exchanger mainly carries an inward current and also plays a role in maintaining the plateau of cardiac action potential.

It is interesting that ultrarapidly activating delayed rectifier K+ channel (encoded by Kv1.5 gene) current (IKur) was found to be functionally present in the atrium10 but not in the ventricle of the human heart.11 It is important for human atrial repolarisation. In addition, acetylcholine-activated K+ channels (IKACh, mediated by muscarinic receptors) are dominantly distributed in the atrium of the human heart and also contribute to human atrial repolarisation (see Figure 1). It has recently been reported that IK.ACh and muscarinic receptor expression are upregulated in AF patients12 and in AF induced in experimental dogs with heart failure.13 Therefore, blockage of IKACh could terminate AF induced by the increased vagal nerve tone. It is believed that blockade of atrial K+ channels (IKur and/or IKACh) could provide an approach for the control of atrial arrhythmias without adverse ventricular effects. Therefore, the compounds targeted to IKur and/or IKACh would be promising agents for developing selective anti-AF drugs.

Atrial-specific Ion Channel Blockers

The pharmaceutical industry has recently made great progress in the development of new antiarrhythmic drugs to treat AF. The design of selective anti-AF drugs pays more attention to compounds that block the atrial-specific IKur and/or IKACh.14,15 It is believed that one of the feared side effects of class III drugs – torsades de pointes arrhythmias – can be overcome by developing a drug that lengthens only the duration of the atrial action potential without increasing the QT interval. Moreover, the dose of the drug needed for effectiveness will be less limited. Several compounds that block hKv1.5 channels and/or native IKur have been developed by Aventis. S9947 (2’-(benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide) and S20951 (2’-{[2-(4-methoxyphenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid 2,4-difluoro-benzylamide) showed remarkable blocking effects on Kv1.5 channel currents expressed in xenopus oocytes and Chinese hamster ovary (CHO) cells, and on IKur in human atrial and rat cardiomyocytes.16In vivo experiments demonstrated that both S9947 and S20951 significantly prolonged the left atrial refractory period in pigs.17

AVE0118 (2’-{[2-(4-methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2- carboxylic acid (2-pyridin-3-yl-ethyl)-amide) is a well-studied IKur blocker developed by Aventis from computationally designed chemical compounds with a structure-based virtual screening procedure for Kv1.5 block.18

This compound was initially found to inhibit human atrial IKur and Ito, and the inhibitory effect on IKACh was then demonstrated in pig atrial myocytes. AVE0118 showed a slight suppression of IKs, IKr and ICa.L in guinea pig cardiac myocytes.19 In addition, AVE0118 was found to significantly prolong the atrial refractory period and completely prevent vulnerability to AF induced by extra stimuli in pigs.20 Importantly, this compound showed excellent anti-AF action in a chronic AF goat model.21 A phase II clinical trial of AVE0118 is under way. NIP-141 and NIP-142 are novel benzopyran derivatives developed by Nissan Chemicals. They inhibit human atrial IKur and Ito.22,23 It was experimentally demonstrated that NIP-142 had an inhibitory effect on IKACh in guinea pig atrium24 and suppressed AF and atrial flutter in a dog model.25 Effects of NIP-141 or NIP-142 on other cardiac ion channels remain undetermined.

A series of diphenyl phosphine oxide (DPO) is a type of potent IKur blocker developed by Merck. These compounds inhibited hKv1.5 with IC50s less than micromolar, suppressed human atrial IKur without affecting Ito, prolonged human atrial action potential and showed a weak inhibitory effect on IK1 and IKs in guinea pig ventricular myocytes.26 DPO-1 was found to significantly prolong the atrial refractory period in non-human primates without prolonging QTc interval27 and to terminate atrial flutter in a dog model.28 Another important IKur blocker recently patented by the authors of this article29,30 is a natural flavone compound (Compound A, 5,7-dihydroxy-4’-methoxyflavone). Compound A was initially discovered in traditional Chinese medicine: Xuelianhua (Saussurea tridactyla). The compound is distributed in plant pigments, universally present in vascular plants and responsible for many of the colours in nature.31 The flavone compounds have been demonstrated to be strong antioxidants that occur naturally in foods and can inhibit carcinogenesis.31,32 Our study showed that, remarkably, Compound A inhibited IKur and Ito in human atrial myocytes and IKACh in guinea pig atrial myocytes and showed a weak inhibition of human cardiac IKs and hERG channels expressed in HEK 293 cells. It had no effect on IK1, INa and ICa.L. Importantly, this compound was found to effectively prolong the atrial refractory period in anaesthetised dogs after intra-duodenal administration without blocking QTc prolongation. Anti-AF study of Compound A is under way.

Multiple Channel Blockers

The Na+-channel blockade is believed to be highly effective in terminating AF by causing primary re-entry waves. 33 Therefore, the INa blocking effect is likely beneficial for a compound that selectively blocks atrial K+ channels. RSD1235 (vernakalant) is a new antiarrhythmic agent developed by Cardiome. Vernakalant showed multiple ion channel-blocking effects, including properties of frequency-dependent Na+-channel blockade and atrial-preferential potassium-channel (IKur and Ito) blockade.34 This compound has been evaluated as an intravenous agent for acute conversion of AF. At a dose of 3mg/kg followed by another 2mg/kg after 15 minutes, vernakalant resulted in 52% conversion of new-onset AF versus 4% with placebo. There was no evidence of QT prolongation or proarrhythmia.35 AZD7009 is a new antiarrhythmic agent developed by AstraZeneca. This compound showed both Na+ and K+ (hERG and IKs) current blocking properties.36 In a canine model, AZD7009 terminated AF and flutter and prevented re-induction. Atrial refractoriness was prolonged to a greater degree than ventricular refractoriness (33 versus 17%) and QT prolongation was modest.37 A recent phase II dose-dependent study demonstrated that AZD7009 resulted in acute conversion in patients with recent onset of AF or flutter. QT prolongation was also observed.38 Therefore, caution is advised when using this compound.

Perspective

A number of promising atrial-specific drugs have been developed from chemically synthesised compounds or natural compounds for anti-AF. Hopefully, it will mark the beginning of a clinically exciting time in anti-AF testing. Despite the advances of numerous alternatives, pharmacological treatment of AF will prevail in the near future.

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