Design, synthesis and evaluation of substituted piperidine based KCNQ openers as novel antiepileptic agents

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1731-1735. doi: 10.1016/j.bmcl.2018.04.040. Epub 2018 Apr 17.

Abstract

Epilepsy is a kind of disease with complicated pathogenesis. KCNQ (Kv7) is a voltage dependent potassium channel that is mostly associated with epilepsy and thus becomes an important target in the treatment of epilepsy. In this paper, a series of substituted piperidine derivatives targeting KCNQ were designed and synthesized by using scaffold hopping and active substructure hybridization. Compounds were evaluated by fluorescence-based thallium influx assay, Rb+ flow assay and electrophysiological patch-clamp assay. Results showed that some compounds possessed more potent potassium channel opening activity than Retigabine. More significantly, compound 11 was found to have good pharmacokinetic profiles in vivo.

Keywords: Epilepsy; KCNQ openers; Retigabine; Substituted piperidine.

MeSH terms

  • Anticonvulsants / chemical synthesis
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Epilepsy / drug therapy*
  • Epilepsy / metabolism
  • Humans
  • KCNQ Potassium Channels / antagonists & inhibitors*
  • KCNQ Potassium Channels / metabolism
  • Molecular Structure
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Anticonvulsants
  • KCNQ Potassium Channels
  • Piperidines
  • piperidine