Simply combining fasudil and lipoic acid in a novel multitargeted chemical entity potentially useful in central nervous system disorders

被引：16

作者：

Chen, Meihui ^{[1
]}

Liu, Qi ^{[1
,2
]}

Liu, Anmin ^{[3
]}

Tan, Min ^{[1
,4
]}

Xie, Zhiyong ^{[1
]}

Uri, Asko ^{[5
]}

Chen, Ziwei ^{[1
]}

Huang, Guangye ^{[1
]}

Sun, Yang ^{[1
]}

Ge, Hu ^{[1
]}

Liu, Peiqing ^{[1
]}

Li, Min ^{[1
,2
]}

Li, Xingshu ^{[1
]}

Wen, Shijun ^{[1
,2
]}

Pi, Rongbiao ^{[1
]}

机构：

[1] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Guangdong, Peoples R China

[2] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Guangzhou 510060, Guangdong, Peoples R China

[3] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Neurosurg, Guangzhou 510275, Guangdong, Peoples R China

[4] Guangzhou Univ Chinese Med, Dept Tradit Chinese Med Chem, Coll Chinese Mat Mad, Guangzhou 510006, Guangdong, Peoples R China

[5] Univ Tartu, Inst Chem, EE-50411 Tartu, Estonia

来源：

RSC ADVANCES | 2014年 / 4卷 / 70期

关键词：

ALZHEIMERS-DISEASE; MASS-SPECTROMETRY; SIGNALING PATHWAY; RAT MODEL; INHIBITORS; LIGANDS; ANALOGS; PLASMA;

D O I：

10.1039/c4ra07337a

中图分类号：

O6 [化学];

学科分类号：

070301 [无机化学];

摘要：

Current drugs against central nervous system (CNS) disorders have limited symptomatic activities, and new approaches with neuroprotective and neurorestorative properties are urgently needed. The complex pathology of CNS disorders requires the development of multitargeted ormultifunctional drugs towards several CNS targets. In the present work, employing the pharmacophore of fasudil, a Rho-associated coil kinase (ROCK) inhibitor, and alpha-lipoic acid (LA), a potent anti-oxidant, we have developed a novel multitargeted and neuroprotective drug, L-F 001. L-F 001 displayed potent inhibition towards both ROCK 1 (IC50 = 1.59 mu M) and ROCK 2 (IC50 = 2.10 mu M) and reduced the actin stress formation. Rat thoracic aorta assay showed that L-F 001 exerted potent vasodilation. Furthermore, the compound was capable of scavenging free radicals, increasing the level of glutathione, and preventing HT 22 cell death caused by glutamate (Glu). Moreover, the new entity had higher brain permeation over fasudil according to in vitro and in vivo blood-brain barrier (BBB) permeability tests. These results indicate that L-F 001 is a promising multifunctional agent for the treatment of CNS disorders.

引用

页码：37266 / 37269

页数：4

共 20 条

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[2]

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