The positive frequency-dependent electrophysiological effects of the IKur inhibitor XEN-D0103 are desirable for the treatment of atrial fibrillation

Abstract

BackgroundSelective inhibitors of Kv1.5 channels are being developed for the treatment of atrial fibrillation (AF).ObjectivesThe purpose of this study was to investigate the effects of the highly selective Kv1.5 inhibitor XEN-D0103 on human atrial action potentials (APs) at high excitation rates and to assess safety.MethodsIntracellular APs (stimulation rates 1–5 Hz) were measured in right atrial trabeculae from patients in sinus rhythm (SR), chronic AF (cAF; AF of >6 months duration), and paroxysmal AF (pAF). The safety and tolerability of XEN-D0103 were tested in a double-blind, randomized, placebo-controlled phase 1 study.ResultsDepending on its concentration, XEN-D0103 elevated the plateau potential. At 1 Hz, XEN-D0103 (3 µM) shortened action potential duration at 90% repolarization (APD90) and effective refractory period (ERP) in SR preparations, but prolonged these parameters in cAF preparations. In SR and pAF preparations, the shortening effects on APD90 and ERP turned into prolongation at high rates. In cAF trabeculae, XEN-D0103 prolonged APD90 and ERP at 2 and 3 Hz. At high rates, more SR and pAF preparations failed to capture excitation in the presence of the drug than in its absence. XEN-D0103 (10 µM) did not significantly affect human ventricular APs. Even with plasma concentrations reaching 7000 ng/mL, XEN-D0103 did not increase ∆∆QTcF (QT interval corrected by the Fridericia formula) in the analysis of electrocardiograms of healthy volunteers, and no subjects receiving an active treatment had a QT or QTcF interval >450 ms, or increase in QTcF from baseline >30 ms.ConclusionAPD prolongation and suppression of APs by XEN-D0103 at high stimulation rates in SR and pAF tissue, but not cAF, could be of therapeutic benefit for reducing AF burden. This concept needs to be confirmed in clinical trials.

Rate-Dependent Role of I Kur in Human Atrial Repolarization and Atrial Fibrillation Maintenance

“…The potential for full inactivation of I Kur suggests that the contribution of the current would decrease at faster rates, as the total amount of time when the cell is depolarized increases and inactivation accumulates. However, recent experimental results using the I Kur -selective blocker XEN-D0103 suggest the opposite, and indicate that the contribution of I Kur to atrial repolarization increases at higher rates (3).…”

Atrial-selective K+ channel blockers: potential antiarrhythmic drugs in atrial fibrillation?

“…Interestingly, the first clinically studied Kv1.5 blocker MK-0448 failed to produce a significant effect on atrial refractoriness in healthy subjects at heart rates up to 150 beats per minute (Pavri et al 2012). One possible explanation for this lack of efficacy could lie in the strong frequencydependency of Kv1.5 blockers that we found in human atrial tissue (J. W. Ford et al 2016). MK-0448 and XEN-D0103 shortened sinus rhythm action potential duration at frequencies below 3 Hz, but clearly prolonged this parameter at faster frequencies (see Figure 2).…”

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

“…The previous work was briefly introduced in the description ofthe potential synthetic derivatives and chemical structure of compounds, and the SAR studies are listed in the corresponding figures in the perspective of medicinal chemistry. As we can see, multiple scaffolds include 5-methoxypsoralen (60,68), tetrahydroindolone (62)(63)(64)(65), benzopyran sulfonamides (70)(71)(72), dihydropyrazolopyrimidine (73,81), and phenylquinazoline (90)(91)(92). Compounds (86)(87)(88) have been reported to be effective in inhibiting Kv1.5, suggesting potential future directions for investigations about Kv1.5 inhibitors.…”