LUF7244, an allosteric modulator/activator of Kv 11.1 channels, counteracts dofetilide-induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model

Br J Pharmacol. 2019 Oct;176(19):3871-3885. doi: 10.1111/bph.14798. Epub 2019 Aug 30.

Abstract

Background and purpose: Kv 11.1 (hERG) channel blockade is an adverse effect of many drugs and lead compounds, associated with lethal cardiac arrhythmias. LUF7244 is a negative allosteric modulator/activator of Kv 11.1 channels that inhibits early afterdepolarizations in vitro. We tested LUF7244 for antiarrhythmic efficacy and potential proarrhythmia in a dog model.

Experimental approach: LUF7244 was tested in vitro for (a) increasing human IKv11.1 and canine IKr and (b) decreasing dofetilide-induced action potential lengthening and early afterdepolarizations in cardiomyocytes derived from human induced pluripotent stem cells and canine isolated ventricular cardiomyocytes. In vivo, LUF7244 was given intravenously to anaesthetized dogs in sinus rhythm or with chronic atrioventricular block.

Key results: LUF7244 (0.5-10 μM) concentration dependently increased IKv11.1 by inhibiting inactivation. In vitro, LUF7244 (10 μM) had no effects on IKIR2.1 , INav1.5 , ICa-L , and IKs , doubled IKr , shortened human and canine action potential duration by approximately 50%, and inhibited dofetilide-induced early afterdepolarizations. LUF7244 (2.5 mg·kg-1 ·15 min-1 ) in dogs with sinus rhythm was not proarrhythmic and shortened, non-significantly, repolarization parameters (QTc: -6.8%). In dogs with chronic atrioventricular block, LUF7244 prevented dofetilide-induced torsades de pointes arrhythmias in 5/7 animals without normalization of the QTc. Peak LUF7244 plasma levels were 1.75 ± 0.80 during sinus rhythm and 2.34 ± 1.57 μM after chronic atrioventricular block.

Conclusions and implications: LUF7244 counteracted dofetilide-induced early afterdepolarizations in vitro and torsades de pointes in vivo. Allosteric modulators/activators of Kv 11.1 channels might neutralize adverse cardiac effects of existing drugs and newly developed compounds that display QTc lengthening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Anti-Arrhythmia Agents / administration & dosage
  • Anti-Arrhythmia Agents / chemistry
  • Anti-Arrhythmia Agents / pharmacology*
  • Atrioventricular Block / drug therapy*
  • Atrioventricular Block / metabolism
  • Atrioventricular Block / pathology
  • Cells, Cultured
  • Disease Models, Animal*
  • Dogs
  • ERG1 Potassium Channel / metabolism*
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Phenethylamines
  • Pyridines / administration & dosage
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Sulfonamides
  • Torsades de Pointes / chemically induced
  • Torsades de Pointes / drug therapy*
  • Torsades de Pointes / pathology

Substances

  • Anti-Arrhythmia Agents
  • ERG1 Potassium Channel
  • LUF7244
  • Phenethylamines
  • Pyridines
  • Sulfonamides
  • dofetilide