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.
复制标题
DOI：
10.1021/acs.jmedchem.0c00168
复制
发表时间：
2020-06-11
影响因子：
7.3
通讯作者：
Chou CJ
中科院分区：
文献类型：
--
作者：
Li X;Himes RA;Prosser LC;Christie CF;Watt E;Edwards SF;Metcalf CS;West PJ;Wilcox KS;Chan SSL;Chou CJ
尽管市场上有25种以上的抗癫痫药物，但大约30%的癫痫患者仍然遭受癫痫发作的折磨。因此，癫痫治疗市场非常需要一种能够帮助耐药患者的突破性药物。在我们之前的研究中，我们发现了一种维生素K类似物2h，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2h的结构，开发了一系列新的维生素K类似物。其中，化合物3d在啮齿动物耐药癫痫模型中显示出充分的保护作用，具有有限的旋转动物运动毒性和良好的PK特性。此外，3d的脑/血浆浓度比表明其对脑具有良好的通透性。结果表明3d可以作为一种潜在的抗癫痫药物在临床上进一步发展。
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.
登录
查看更多内容
影响因子：
3.3
作者：
Rahn, J. J.;Bestman, J. E.;Josey, B. J.;Inks, E. S.;Stackley, K. D.;Rogers, C. E.;Chou, C. J.;Chan, S. S. L.
通讯作者：
Chan, S. S. L.
影响因子：
2.2
作者：
Barton, ME;Klein, BD;White, HS
通讯作者：
White, HS
影响因子：
5.6
作者：
Lyczkowski, DA;Pfeifer, HH;Thiele, EA
通讯作者：
Thiele, EA
影响因子：
4.4
作者：
Kehne, John H.;Klein, Brian D.;Sharma, Shalini
通讯作者：
Sharma, Shalini
影响因子：
5.6
作者：
Metcalf CS;West PJ;Thomson KE;Edwards SF;Smith MD;White HS;Wilcox KS
通讯作者：
Wilcox KS