Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators

Bioorg Med Chem Lett. 2019 Mar 15;29(6):791-796. doi: 10.1016/j.bmcl.2019.01.027. Epub 2019 Jan 23.

Abstract

The present study describes the discovery and characterization of a series of 5-aryl-2H-tetrazol-3-ylacetamides as G protein-gated inwardly-rectifying potassium (GIRK) channels activators. Working from an initial hit discovered during a high-throughput screening campaign, we identified a tetrazole scaffold that shifts away from the previously reported urea-based scaffolds while remaining effective GIRK1/2 channel activators. In addition, we evaluated the compounds in Tier 1 DMPK assays and have identified a (3-methyl-1H-pyrazol-1-yl)tetrahydrothiophene-1,1-dioxide head group that imparts interesting and unexpected microsomal stability compared to previously-reported pyrazole head groups.

Keywords: Activator; G protein-regulated inwardly-rectifying potassium channel; GIRK; Tetrazole.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Animals
  • Drug Discovery*
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / agonists*
  • HEK293 Cells
  • Humans
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • Tetrazoles / chemical synthesis
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacology*

Substances

  • Acetamides
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • KCNJ6 protein, human
  • Pyrazoles
  • Tetrazoles