Stefan Peukert

Electrophysiological and antiarrhythmic effects of the novel I(Kur) channel blockers, S9947 and S20951, on left vs. right pig atrium in vivo in comparison with the I(Kr) blockers dofetilide, azimilide, d,l-sotalol and ibutilide.

Abstract. Inhibition of the cardiac Kv1.5 channel, the molecular base for the human cardiac ultrarapid delayed rectifier potassium current (IKur), is considered a new promising atrial selective antiarrhythmic concept since this channel is presumed to contribute to atrial but not ventricular repolarization in the human heart. In a previous study in pigs we found clear baseline differences in refractoriness between left and right atrium with shorter effective refractory periods (ERPs) of the left atrium associated with a high left atrial vulnerability for tachyarrhythmias. In this newly established model we compared atrial and ventricular effects of two novel IKur blockers, S9947 and S20951, with the IKr blockers dofetilide, azimilide, ibutilide and d,l-sotalol. In pentobarbital anesthetized pigs (n=45) we determined ERPs in the free walls of both atria with the S1-S2-stimulus method at three basic cycle lengths (BCL 240/300/400xa0ms) and QTc-intervals. The incidence of atrial tachyarrhythmias triggered by the S2-extrastimulus of the left atrium was evaluated (referred to as left atrial vulnerability).In contrast to IKr blockade, IKur blockade had no effect on the QT-interval, but prolonged the atrial ERP. The IKur blockers were significantly stronger on left atrial ERP, IKr blockers on right atrial ERP (P<0.05 for all compounds tested). At 240xa0ms BCL the IKur blocker S20951, 3xa0mg/kg, prolonged left vs. right atrial ERP by 28±5xa0ms vs. 12±3xa0ms and S9947, 3xa0mg/kg, by 45±7xa0ms vs. 19±6xa0ms. By contrast the effect of dofetilide, 10xa0µg/kg, was stronger on the right than left atrium (47±6xa0ms vs. 25±2xa0ms), a profile also found with azimilide (5xa0mg/kg, 43±3xa0ms vs. 17±3xa0ms), ibutilide (15xa0µg/kg, 70±10xa0ms vs. 29±4xa0ms) and d,l-sotalol (1.5xa0mg/kg, 57±6xa0ms vs. 36±4xa0ms). The IKur blockers, S20951and S9947, significantly decreased left atrial vulnerability (–82% and –100%, respectively, P<0.01) in contrast to the selective IKr blocker dofetilide (–14%; n.s.).In conclusion, IKur and IKr blockers showed substantial differences in their atrial and ventricular actions in pigs. IKr blockers were stronger on right atrial ERP, IKur blockers on left atrial ERP, suggesting interatrial differences in the expression of potassium channels. In contrast to selective IKr blockade, IKur blockade inhibited left atrial vulnerability and had no effect on the QT-interval. Thus, blockade of IKur seems to be a promising atrial selective antiarrhythmic concept.

Blockers of the Kv1.5 Channel for the Treatment of Atrial Arrhythmias [1]

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.

New inhibitors of poly(ADP-ribose) polymerase (PARP)

Poly(ADP-ribose) polymerase-1 (PARP-1), the most prominent member of the PARP family, is a DNA-binding protein that is activated by nicks in DNA occurring during inflammation, ischaemia, neurodegeneration or cancer therapy. Activated PARP-1 consumes NAD+ that is cleaved into nicotinamide and ADP-ribose and polymerises the latter onto nuclear acceptor proteins. This highly energy consuming process is pivotal for the maintenance of genomic stability although over-activation can culminate in cell dysfunction and necrosis. Therefore, PARP-1 is regarded as a promising target for the development of drugs useful in various forms of inflammation, ischaemia–reperfusion injury and as an adjunct in cancer therapy. This review summarises the structural classes of known PARP-1 inhibitors, with a focus on new inhibitors published for this target, between 2002 and July 2004. The chemistry and biological data disclosed in these patent applications are discussed in light of new structural knowledge of the catalytic domain of the PARP family and recent work with potent inhibitors demonstrating the effects of PARP inhibition in various animal disease models.

Blockers of the Kv1.5 channel for the treatment of atrial arrhythmias

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 treatments. The voltage-gated potassium channel Kv1.5 is regarded as a promising target for the development of new atrial selective drugs with fewer side effects. This review summarises patents claiming such compounds. The chemistry and biological data disclosed in these patents are discussed in light of recent work demonstrating the antiarrhythmic effects of Kv1.5 blockers in vivo.

The discovery of Kv1.5 blockers as a case study for the application of virtual screening approaches.

Different virtual screening techniques are available as alternatives to high throughput screening. These different techniques have been rarely used together on the same target. We had the opportunity to do so in order to discover novel blockers of the voltage-dependent potassium channel Kv1.5, a potential target for the treatment of atrial fibrillation. Our corporate database was searched, using a protein-based pharmacophore, derived from a homology model, as query. As a result, 244 molecules were screened in vitro, 19 of them (7.8%) were found to be active. Five of them, belonging to five different chemical classes, exhibited IC50 values under 10 microM. The performance of this structure-based virtual screening protocol has been compared with those of similarity and ligand-based pharmacophore searches. The analysis of the results supports the conventional wisdom of using as many virtual screening techniques as possible in order to maximize the chance of finding as many chemotypes as possible.