Lead compound optimization strategy (5)-reducing the hERG cardiac toxicity in drug development / 药学学报

The potassium channel encoded by the human ether-a-go-go related gene (hERG) plays a very important role in the physiological and pathological processes in human. hERG potassium channel determines the outward currents which facilitate the repolarization of the myocardial cells. Some drugs were withdrawn from the market for the serious side effect of long QT interval and arrhythmia due to blockade of hERG channel. The strategies for lead compound optimization are to reduce inhibitory activity of hERG potassium channel and decrease cardiac toxicity. These methods include reduction of lipophilicity and basicity of amines, introduction of hydroxyl and acidic groups, and restricting conformation.