Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel

Eur J Med Chem. 2015 Dec 1:106:50-9. doi: 10.1016/j.ejmech.2015.10.032. Epub 2015 Oct 21.


We synthesized and evaluated a series of compounds for their allosteric modulation at the Kv11.1 (hERG) channel. Most compounds were negative allosteric modulators of [(3)H]dofetilide binding to the channel, in particular 7f, 7h-j and 7p. Compounds 7f and 7p were the most potent negative allosteric modulators amongst all ligands, significantly increasing the dissociation rate of dofetilide in the radioligand kinetic binding assay, while remarkably reducing the affinities of dofetilide and astemizole in a competitive displacement assay. Additionally, both 7f and 7p displayed peculiar displacement characteristics with Hill coefficients significantly distinct from unity as shown by e.g., dofetilide, further indicative of their allosteric effects on dofetilide binding. Our findings in this investigation yielded several promising negative allosteric modulators for future functional and clinical research with respect to their antiarrhythmic propensities, either alone or in combination with known Kv11.1 blockers.

Keywords: Antiarrhythmia; K(v)11.1 blockers; K(v)11.1(hERG) channel; Negative allosteric modulator; Radioligand binding assay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Allosteric Regulation / drug effects
  • Arrhythmias, Cardiac / drug therapy
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / chemistry
  • Ether-A-Go-Go Potassium Channels / metabolism*
  • HEK293 Cells
  • Humans
  • Kinetics
  • Molecular Structure
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology*
  • Phenethylamines / chemistry
  • Phenethylamines / metabolism
  • Potassium Channel Blockers / chemical synthesis
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / pharmacology*
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism


  • 2-(4-benzoylphenoxy)-N-(pyridin-3-yl)acetamide
  • Acetamides
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • Naphthyridines
  • Phenethylamines
  • Potassium Channel Blockers
  • Pyridines
  • Sulfonamides
  • VU0405601
  • dofetilide