School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266071, China.
Department of Chemistry and Biochemistry, College of Charleston, 66 George Street, Charleston, South Carolina 29424, United States.
J Med Chem. 2020 Jun 11;63(11):5865-5878. doi: 10.1021/acs.jmedchem.0c00168. Epub 2020 May 22.
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, , 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 . Among these, compound 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 indicates its excellent permeability into the brain. The resulting data shows that can be further developed as a potential antiseizure drug in the clinic.
尽管市场上有超过 25 种抗癫痫药物，但仍有约 30%的癫痫患者仍遭受癫痫发作的困扰。因此，癫痫治疗市场急需一种突破性药物来帮助耐药患者。在我们之前的研究中，我们发现了一种维生素 K 类似物 ，它在斑马鱼和小鼠癫痫模型中显示出适度的抗癫痫活性。然而，由于其药代动力学特征，该化合物存在局限性。在本研究中，我们通过修饰 的结构开发了一系列新的维生素 K 类似物。在这些化合物中，化合物 在具有有限的旋转杆运动毒性和良好的药代动力学特性的啮齿动物耐药性癫痫发作模型中显示出完全的保护作用。此外， 的脑/血浆浓度比表明其具有优异的脑渗透性。结果数据表明 可以进一步开发为临床潜在的抗癫痫药物。
