Development of Second-Generation Small-Molecule RhoA Inhibitors with Enhanced Water Solubility, Tissue Potency, and Significant in vivo Efficacy
文献类型：期刊论文
| 作者 | Ma, Sheng3; Deng, Jing2; Li, Baoli2; Li, Xiujiang2; Yan, Zhaowei3; Zhu, Jin2; Chen, Gang1; Wang, Zhong1; Jiang, Hualiang2,4 ; Miao, Liyan3
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| 刊名 | CHEMMEDCHEM
 |
| 出版日期 | 2015-01 |
| 卷号 | 10期号:1页码:193-206 |
| 关键词 | cardiovascular agents RhoA inhibitors subarachnoid hemorrhage water solubility vasorelaxation |
| ISSN号 | 1860-7179 |
| DOI | 10.1002/cmdc.201402386 |
| 文献子类 | Article |
| 英文摘要 | RhoA, a member of the Rho GTPases, is involved in a variety of cellular functions and could be a suitable therapeutic target for the treatment of cardiovascular diseases. However, few small-molecule RhoA inhibitors have been reported. Based on our previously reported lead compounds, 32 new 2-substituted quinoline (or quinoxaline) derivatives were synthesized and tested in biological assays. Six compounds showed high RhoA inhibitory activities, with IC50 values of 1.17-1.84M. Among these, (E)-3-(3-(ethyl(quinolin-2-yl)amino)phenyl)acrylic acid (26b) and (E)-3-(3-(butyl(quinolin-2-yl)amino)phenyl)acrylic acid (26d) demonstrated noticeable vasorelaxation effects against phenylephrine-induced contraction in thoracic aorta artery rings, and compound 26b had good water solubility and showed significant in vivo efficacy, which was similar to that of 5-(1,4-diazepane-1-sulfonyl)isoquinoline (fasudil) in a subarachnoid hemorrhage-cardiovascular model. To the best of our knowledge, compound 26b is the first example of a small- molecule RhoA inhibitor with potent in vivo efficacy, which could serve as a good lead for designing cardiovascular agents. |
| WOS关键词 | ANEURYSMAL SUBARACHNOID HEMORRHAGE ; RIBOSYLATING C3 EXOENZYME ; SMOOTH-MUSCLE-CELLS ; CLOSTRIDIUM-BOTULINUM ; CRYSTAL-STRUCTURE ; KINASE ; PROTEIN ; FASUDIL ; THERAPY ; CONTRACTION |
| 资助项目 | National Natural Science Foundation of China[21222211] ; National Natural Science Foundation of China[21372001] ; National Natural Science Foundation of China[91313303] ; National Natural Science Foundation of China[81202394] ; Ministry of Education of China's Program for New Century Excellent Talents in University[NCET-12-0853] ; Fundamental Research Funds for the Central Universities of China[00000000] ; Applied Basic Research Programs of Suzhou Sci-tech Bureau, China[SYS201219] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000346766700019 |
| 出版者 | WILEY-V C H VERLAG GMBH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276780]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Wang, Zhong |
| 作者单位 | 1.Soochow Univ, Affiliated Hosp 1, Dept Neurosurg, Suzhou 215006, Shanghai, Peoples R China; 2.E China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China; 3.Soochow Univ, Dept Clin Pharmacol Res Lab, Affiliated Hosp 1, Suzhou 215006, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ma, Sheng,Deng, Jing,Li, Baoli,et al. Development of Second-Generation Small-Molecule RhoA Inhibitors with Enhanced Water Solubility, Tissue Potency, and Significant in vivo Efficacy[J]. CHEMMEDCHEM,2015,10(1):193-206. |
| APA | Ma, Sheng.,Deng, Jing.,Li, Baoli.,Li, Xiujiang.,Yan, Zhaowei.,...&Li, Jian.(2015).Development of Second-Generation Small-Molecule RhoA Inhibitors with Enhanced Water Solubility, Tissue Potency, and Significant in vivo Efficacy.CHEMMEDCHEM,10(1),193-206. |
| MLA | Ma, Sheng,et al."Development of Second-Generation Small-Molecule RhoA Inhibitors with Enhanced Water Solubility, Tissue Potency, and Significant in vivo Efficacy".CHEMMEDCHEM 10.1(2015):193-206. |
入库方式： OAI收割
来源：上海药物研究所
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