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

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 (IKr). The block of IKr can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike IKr, the role of the slow component of the delayed rectifier potassium current (IKs) becomes significant only at faster heart rate. Therefore selective blockers of IKs could prolong APD with a reduced propensity to cause pro-arrhythmic side effects. This report describes structure–activity relationships (SARs) of a series of IKs inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC50 ≥30 nM) and up to 40-fold IKs/IKr selectivity.