Isoindolinone compounds active as Kv1.5 blockers identified using a multicomponent reaction approach

Bioorg Med Chem Lett. 2016 Apr 15;26(8):2023-9. doi: 10.1016/j.bmcl.2016.02.081. Epub 2016 Mar 2.

Abstract

A series of isoindolinone compounds have been developed showing good in vitro potency on the Kv1.5 ion channel. By modification of two side chains on the isoindolinone scaffold, metabolically stable compounds with good in vivo PK profile could be obtained leaving the core structure unsubstituted. In this way, low microsomal intrinsic clearance (CLint) could be achieved despite a relatively high logD. The compounds were synthesized using the Ugi reaction, in some cases followed by Suzuki and Diels-Alder reactions, giving a diverse set of compounds in a small number of reaction steps.

Keywords: Atrial fibrillation; IKur; Isoindolinones; Kv1.5; Multicomponent reactions; Structure activity relationship (SAR).

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Humans
  • Isoindoles / chemical synthesis
  • Isoindoles / chemistry
  • Isoindoles / pharmacology*
  • Kv1.5 Potassium Channel / antagonists & inhibitors*
  • Mice
  • Models, Animal
  • Molecular Structure
  • Potassium Channel Blockers / chemical synthesis
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / pharmacology*
  • Structure-Activity Relationship

Substances

  • Isoindoles
  • KCNA5 protein, human
  • Kv1.5 Potassium Channel
  • Potassium Channel Blockers