Discovery of the First Vitamin K Analogue as a Potential Treatment of Pharmacoresistant Seizures
Xiaoyang Li, Richard A. Himes, Lyndsey C. Prosser, Charleston F. Christie, Emma Watt, Sharon F. Edwards, Cameron S. Metcalf, Peter J. West, Karen S. Wilcox, Sherine S.L. Chan, C. James Chou
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.