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Online ISSN: 1860-7187
October 13, 2011
VIP: Understanding of Molecular Substructures that Contribute to hERG K+ Channel Blockade: Synthesis and Biological Evaluation of E-4031 Analogues
Maris Vilums, Jeroen Overman, Elisabeth Klaasse, Olaf Scheel, Johannes Brussee, Adriaan P. IJzerman*
Several drugs have been withdrawn from the market or failed in late-stage clinical trials over the past two decades because cardiac arrhythmia was a side effect of treatment. In most cases this was due to drug interaction with the human ether-à-go-go-related gene (hERG) potassium ion channel. This finding received increasing attention from regulatory agencies and pharmaceutical industries to the extent that nowadays every new drug lead is tested for hERG blockade during its development. If a lead compound is found to be active at the hERG channel, attempts are made to “repair” the molecule; otherwise, the lead compound is removed from the pipeline entirely.
A group of researchers led by Adriaan P. IJzerman at the Leiden/Amsterdam Center for Drug Research, University of Leiden (Netherlands) have looked at this problem from another point of view, changing the paradigm from “fighting the problem” to “preventing the problem”. Instead of trying to remove hERG activity from a lead compound they looked directly at the structure–activity relationships on the hERG ion channel itself. They evaluated a series of derivatives based on the class III antiarrhythmic agent E-4031, which has high hERG affinity. Their study provides practical information on the molecular determinants that could be omitted from or applied to new drugs in order to reduce the hERG ion channel blockade. Pharmaceutical industries and academic groups may use these considerations in the design of new drug entities; doing so could decrease cardiotoxicity in the early stages of drug development, eventually increasing drug safety and reducing development costs.
Received July 27, 2011; published online September 15, 2011, DOI: 10.1002/cmdc.201100366.