Discovery of the first Vitamin K analog as a potential treatment of pharmacoresistant seizures
| Autor: | Xiaoyang Li, Emma Watt, Peter J. West, Cameron S. Metcalf, Charleston F Christie, Richard A. Himes, C. James Chou, Sharon F. Edwards, Sherine S.L. Chan, Karen S. Wilcox, Lyndsey C Prosser |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Drug
Male Vitamin K Cell Survival media_common.quotation_subject Drug Evaluation Preclinical Administration Oral Vitamin k Pharmacology 01 natural sciences Article 03 medical and health sciences Epilepsy Mice Structure-Activity Relationship Pharmacokinetics Cytochrome P-450 Enzyme System Seizures Cell Line Tumor Drug Discovery medicine Epilepsy therapy Animals Humans Zebrafish 030304 developmental biology media_common 0303 health sciences Antiseizure drug Chemistry Brain medicine.disease 0104 chemical sciences Isoenzymes 010404 medicinal & biomolecular chemistry Disease Models Animal Plasma concentration Toxicity Molecular Medicine Anticonvulsants Half-Life |
| Zdroj: | J Med Chem |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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