2. Academic Validation
  3. Discovery of the First Vitamin K Analogue as a Potential Treatment of Pharmacoresistant Seizures

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

  • J Med Chem. 2020 Jun 11;63(11):5865-5878. doi: 10.1021/acs.jmedchem.0c00168.
Xiaoyang Li 1,  Richard A Himes 2,  Lyndsey C Prosser 2,  Charleston F Christie 3,  Emma Watt 2,  Sharon F Edwards 4,  Cameron S Metcalf 4,  Peter J West 4,  Karen S Wilcox 4,  Sherine S L Chan 3 5,  C James Chou 3 5
Affiliations

Affiliations

  • 1 School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266071, China.
  • 2 Department of Chemistry and Biochemistry, College of Charleston, 66 George Street, Charleston, South Carolina 29424, United States.
  • 3 Neuroene Therapeutics, Mount Pleasant, South Carolina 29464, United States.
  • 4 Anticonvulsant Drug Development (ADD) Program, Department of Pharmacology & Toxicology, University of Utah, Salt Lake City, Utah 84112, United States.
  • 5 Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425, United States.
PMID: 32390424 DOI: 10.1021/acs.jmedchem.0c00168
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.

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