PUBLICATION
Discovery of the first Vitamin K analog as a potential treatment of pharmacoresistant seizures
- Authors
- 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.
- ID
- ZDB-PUB-200512-4
- 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.
Citation
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. (2020) Discovery of the first Vitamin K analog as a potential treatment of pharmacoresistant seizures. Journal of medicinal chemistry. 63(11):5865-5878.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping