|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.
|Source:||Journal of medicinal chemistry 63(11): 5865-5878 (Journal)|
|Registered Authors:||Chan, Sherine|
|PubMed:||32390424 Full text @ J. Med. Chem.|
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.
ABSTRACTDespite 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.
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