Novel, Potent Inhibitors of Human Kv1.5 K⁺ Channels and Ultrarapidly Activating Delayed Rectifier Potassium Current

Abstract

We have identified a series of diphenyl phosphine oxide (DPO) compounds that are potent frequency-dependent inhibitors of cloned human Kv1.5 (hKv1.5) channels. DPO inhibited hKv1.5 expressed in Chinese hamster ovary cells in a concentrationdependent manner preferentially during channel activation and slowed the deactivating tail current, consistent with a predominant open-channel blocking mechanism. Varying kinetics of DPO interaction with Kv1.5 channels resulted in differing potencies and frequency dependencies of inhibition that were comparable for both expressed hKv1.5 current and native ultrarapidly activating delayed rectifier potassium current (I Kur ) in human atrial myocytes. Selectivity of DPO versus other cardiac K ϩ channels was demonstrated in human atrial myocytes (I Kur versus transient outward potassium current) and guinea pig ventricular myocytes [I Kur versus rapidly activating delayed rectifier potassium current (I Kr ), slowly activating delayed rectifier potassium current (I Ks ) and inward rectifier potassium current (I K1 ), and one compound (DPO-1) was shown to be 15-fold more selective for Kv1.5 versus Kv3.1 channels expressed in Xenopus oocytes. DPO-1 also prolonged action potentials of isolated human atrial but not ventricular myocytes, in contrast to the effect of a selective I Kr blocker. The selectivity and kinetics of inhibition hKv1.5 and I Kur by DPO and the resulting selective prolongation of atrial repolarization could provide an effective profile for treatment of supraventricular arrhythmias.

Role of Protein Kinase Cζ and Its Adaptor Protein p62 in Voltage-Gated Potassium Channel Modulation in Pulmonary Arteries

“…5B) as described previously (Cogolludo et al, 2003). The K V 1.5 channel blocker DPO-1 (Lagrutta et al, 2006) inhibited K V currents in rat PASMCs. In the presence of DPO-1, U46619 produced no further inhibitory effects (Fig.…”

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

“…However, there is in silico and experimental evidence that the electrophysiological and antiarrhythmic effects of I Kur blockade are modulated by the time-and voltage-dependent kinetics of block. Using a family of I Kur -selective diphenyl phosphine oxide compounds, Lagrutta et al (25) were able to show that I Kur blocking potency and frequency dependence were functions of blocking kinetics, with open state blockers being the most effective I Kur antagonists. Several other molecules, including vernakalant and experimental compounds like zatebradine, loratadine, and bisindolylmaleimide, have also been shown to block I Kur preferentially in the open state (19,(26)(27)(28).…”

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

“…A number of K V 1.5 channel inhibitors have been or are in development for treating AF, and the applicability of I Kur inhibition as a valid approach for treating AF is likely to be clarified in the future. Some of these compounds are AVE0118 (IC 50 1.1 M), which also has affinity for I to and I KAch (142); DPO-1 as a use-dependent open I Kur channel blocker with some affinity for I K1 and I Ks (230,361); and more selective compounds such as XEN-D0101 and XEN-D0103 with human atrial I Kur IC 50 values of 241 and 154 nM, respectively (125). It has generally proven difficult to obtain good selectivity among K v channel subtypes, as many drugs interact with highly conserved residues in the central cavity.…”