Tetrahydronaphthalene-derived amino alcohols and amino ketones as potent and selective inhibitors of the delayed rectifier potassium current IKs

Abstract

Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current ( I Kr). The block of I Kr can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike I Kr, the role of the slow component of the delayed rectifier potassium current ( I Ks) becomes significant only at faster heart rate. Therefore selective blockers of I Ks could prolong APD with a reduced propensity to cause pro-arrhythmic side effects. This report describes structure–activity relationships (SARs) of a series of I Ks inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC 50 ≥30 nM) and up to 40-fold I Ks/ I Kr selectivity.