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

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.