ZFIN ID: ZDB-PUB-200512-4
Discovery of the first Vitamin K analog as a potential treatment of pharmacoresistant seizures
Li, X., Himes, R.A., Prosser, L.C., Christie, C.F., Watt, E., Edwards, S.F., Metcalf, C., West, P., Wilcox, K., Chan, S.S.L., Chou, C.J.
Date: 2020
Source: Journal of medicinal chemistry   63(11): 5865-5878 (Journal)
Registered Authors: Chan, Sherine
Keywords: none
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
PubMed: 32390424 Full text @ J. Med. Chem.
Despite the availability of more than 25 anti-seizure 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 analog, 2h, which displayed modest anti-seizure activity in zebrafish and mouse seizure models. However, there were limitations for this compound due to its pharmacokinetic profile. In this study, we developed a new series of vitamin K analogs 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 PK properties. Furthermore, the brain/plasma concentration ratio of 3d indicates its excellent permeability to the brain. The resulting data shows 3d can be further developed as a potential anti-seizure drug in the clinic.