Celecoxib Analog SC-791's interaction with hERG Potassium Channel
Taillie, Keith T.
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The human ether-a-go-go related gene (hERG) codes for a K + channel that is crucial for repolarization in cardiomyocytes. Reduced channel current (genetic or drug induced) can cause Long QT Syndrome followed by the potentially lethal arrhythmia Torsades de Pointes . NSAIDs (Non-Steroidal Anti Inflammatory Drugs), arthritis and general analgesic pharmaceuticals, are known for their pro-thrombotic risk but have recently been indicated in arrhythmic risk as well. Celecoxib (Celebrex), a selective cyclooxygenase-2 inhibitor NSAID, has been shown to inhibit the hERG channel at physiologically relevant concentrations in vitro , as well as cause arrhythmia in Drosophila heart and in cultured rat cardiomyocytes. These findings have revealed the importance of investigating the arrhythmic risk of other common NSAIDs considering their prevalence as both prescribed and "Over the counter" drugs. Using whole-cell patch clamp methods, HEK-293 cells with stable expression of wild type hERG DNA were perfused with doses of common NSAIDs Ibuprofen, Diclofenac, Aspirin, and Naproxen, and Celecoxib Analog SC-791. Long term recordings indicate that SC-791 inhibits hERG at doses similar to those for Celecoxib in a concentration dependent manner. The remaining NSAIDs showed little inhibition or even a slight increase in hERG current at doses higher than those found in a clinical setting. The mechanism of inhibition by SC-791was examined and appeared to be very similar to that for Celebrex. Both drugs are hERG gating modifiers that accelerate activation, inactivation, and recovery from inactivation. From the results it can be concluded that Celecoxib's inhibition of the hERG channel is independent of its COX-2 inhibition effects. This is contrary to the common "pore block" mechanism exhibited by most hERG inhibitors. SC-791's similar hERG channel inhibition compared to Celecoxib may give insight to scientists to further understand the pharmacophore of the hERG channel and Celecoxib. Differences in arrhythmic potential between SC-791 and Celecoxib shown in animal studies may be better explained and give a better understanding of the correlation between drug - ion channel interactions and arrhythmia. Drug developers may be able to produce safer pharmaceuticals by comparing the molecular structures, ion channel interactions, and arrhythmic risks between SC-791 and Celecoxib.