Role of hERG potassium channel assays in drug development.
Numerous structurally and functionally unrelated drugs block the hERG potassium channel. HERG channels are involved in cardiac action potential repolarization, and reduced function of hERG lengthens ventricular action potentials, prolongs the QT interval in an electrocardiogram, and increases the risk for potentially fatal ventricular arrhythmias. In order to reduce the risk of investing resources in a drug candidate that fails preclinical safety studies because of QT prolongation, it is important to screen compounds for activity on hERG channels early in the lead optimization process. A number of hERG assays are available, ranging from high throughput binding assays on stably expressed recombinant channels to very time consuming electrophysiological examinations in cardiac myocytes. Depending on the number of compounds to be tested, binding assays or functional assays measuring membrane potential or Rb(+) flux, combined with electrophysiology on a few compounds, can be used to efficiently develop the structure-function relationship of hERG interactions.
Priest
Birgit T
BT
Department of Ion Channels, Merck Research Laboratories, Rahway, New Jersey, USA. birgit_priest@merck.com
Bell
Ian M
IM
Garcia
Maria L
ML
D000889:Anti-Arrhythmia Agents / Q000737:chemistry; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels