Discovery and SAR of a novel series of GIRK1/2 and GIRK1/4 activators

Bioorg Med Chem Lett. 2013 Sep 15;23(18):5195-8. doi: 10.1016/j.bmcl.2013.07.002. Epub 2013 Jul 18.

Abstract

This Letter describes a novel series of GIRK activators identified through an HTS campaign. The HTS lead was a potent and efficacious dual GIRK1/2 and GIRK1/4 activator. Further chemical optimization through both iterative parallel synthesis and fragment library efforts identified dual GIRK1/2 and GIRK1/4 activators as well as the first examples of selective GIRK1/4 activators. Importantly, these compounds were inactive on GIRK2 and other non-GIRK1 containing GIRK channels, and SAR proved shallow.

Keywords: Activators; GIRK; K(ir)3.x; Thallium flux.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism*
  • Mice
  • Molecular Probes / chemical synthesis
  • Molecular Probes / chemistry
  • Molecular Probes / pharmacology*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Molecular Probes