Discovery of a novel Kv7 channel opener as a treatment for epilepsy

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4941-4944. doi: 10.1016/j.bmcl.2015.04.074. Epub 2015 May 1.


Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.

Keywords: Amygdala-kindled seizure; Dimethoxypyrimidine; KCNQ; Kv7 channel opener; Maximal electroshock; PF-05020182; Pentylenetetrazole-induced seizure.

MeSH terms

  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Electroshock
  • Epilepsy / drug therapy*
  • Humans
  • Ion Channel Gating / drug effects*
  • KCNQ2 Potassium Channel / agonists
  • KCNQ2 Potassium Channel / metabolism*
  • Microsomes / drug effects
  • Molecular Structure
  • Piperidines / administration & dosage
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • Structure-Activity Relationship


  • KCNQ2 Potassium Channel
  • PF-05020182
  • Piperidines
  • Pyrimidines