Discovery of the First Vitamin K Analogue as a Potential Treatment of Pharmacoresistant Seizures

J Med Chem. 2020 Jun 11;63(11):5865-5878. doi: 10.1021/acs.jmedchem.0c00168. Epub 2020 May 22.

Abstract

Despite the availability of more than 25 antiseizure drugs on the market, approximately 30% of patients with epilepsy still suffer from seizures. Thus, the epilepsy therapy market has a great need for a breakthrough drug that will aid pharmacoresistant patients. In our previous study, we discovered a vitamin K analogue, 2h, which displayed modest antiseizure activity in zebrafish and mouse seizure models. However, there are limitations to this compound due to its pharmacokinetic profile. In this study, we develop a new series of vitamin K analogues by modifying the structure of 2h. Among these, compound 3d shows full protection in a rodent pharmacoresistant seizure model with limited rotarod motor toxicity and favorable pharmacokinetic properties. Furthermore, the brain/plasma concentration ratio of 3d indicates its excellent permeability into the brain. The resulting data shows that 3d can be further developed as a potential antiseizure drug in the clinic.

Publication types

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

MeSH terms

  • Administration, Oral
  • Animals
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacokinetics
  • Anticonvulsants / pharmacology
  • Anticonvulsants / therapeutic use*
  • Brain / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cytochrome P-450 Enzyme System / chemistry
  • Cytochrome P-450 Enzyme System / metabolism
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Male
  • Mice
  • Seizures / drug therapy*
  • Seizures / pathology
  • Structure-Activity Relationship
  • Vitamin K / analogs & derivatives*
  • Vitamin K / pharmacokinetics
  • Vitamin K / pharmacology
  • Vitamin K / therapeutic use
  • Zebrafish

Substances

  • Anticonvulsants
  • Isoenzymes
  • Vitamin K
  • Cytochrome P-450 Enzyme System