August 6, 2012
Heteroarylsulfonamides may reduce atrial fibrillation. Voltage-gated potassium channels play a prominent role in excitable cells, particularly in the heart, where they are responsible for maintaining cardiac rhythm and repolarization. In heart rhythm disorders, such as atrial fibrillation, normal cardiac rhythm is interrupted by electrical re-entry circuits, creating irregular electrical activity in the heart and asynchronous contractions of cardiac tissue.
Nonselective blockade of multiple cardiac ion channels is used to decrease atrial fibrillation events by increasing the effective refractory period. hERG-mediated side effects, including torsade de pointes and sudden cardiac death, however, are complications of nonselective channel blockade. (hERG is the human ether-à-go-go–related gene.) The side effects are primarily the result of the hERG channel's critical role in ventricular repolarization.
The Kv1.5 channel, on the other hand, plays a critical role in repolarizing the heart’s atrial chamber, but it has no role in repolarizing the ventricular chamber. In addition, the Kv1.5 channel is not functionally expressed in the ventricular chamber. It has been hypothesized that a compound with a high degree of selectivity for Kv1.5 over hERG would provide an effective treatment for atrial fibrillation with minimal hERG-related risks.
Inventors E. Dupont-Passelaigue, I. Le Roy, and C. Pignier disclose a series of heteroarylsulfonamides that are useful as Kv1.5 channel inhibitors for treating atrial fibrillation. Key classes of these sulfonamides are shown in Figure 1.
Figure 2 contains some of the more effective molecules.
(Pierre FabrÉ Medicament [France].WIPO Patent Publication WO2012069503, May 31, 2012; Benjamin Blass)
This patent was originally reviewed in ACS Medicinal Chemistry Letters.