Pseudosaccharin amines as potent and selective KV1.5 blockers

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4983-4986. doi: 10.1016/j.bmcl.2015.02.066. Epub 2015 Mar 7.

Abstract

Phenethyl aminoheterocycles like compound 1 were known to be potent I(Kur) blockers although they lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin amines. Compounds such as 14, 17d and 21c were found to be potent K(V)1.5 blockers and selective over other cardiac ion channels. These compounds had potent pharmacodynamic activity, however, they also showed off-target activities such as hemodynamic effects.

Keywords: AERP; Atrial fibrillation; I(Kur); K(V)1.5; Phenethylamine.

MeSH terms

  • Amines / chemical synthesis
  • Amines / chemistry
  • Amines / pharmacology*
  • Animals
  • Blood Pressure / drug effects
  • Cyclohexanes / chemistry
  • Cyclohexanes / pharmacology
  • Dose-Response Relationship, Drug
  • Humans
  • Kv1.5 Potassium Channel / antagonists & inhibitors*
  • Kv1.5 Potassium Channel / metabolism
  • Mice
  • Molecular Structure
  • Potassium Channel Blockers / chemical synthesis
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / pharmacology*
  • Rabbits
  • Rats
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Structure-Activity Relationship

Substances

  • Amines
  • Cyclohexanes
  • Kv1.5 Potassium Channel
  • Potassium Channel Blockers
  • Spiro Compounds