SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models
文献类型：期刊论文
| 作者 | Yan, Pang-ke1; Zhang, Li-na1; Feng, Ying1; Qu, Hui1; Qin, Li1; Zhang, Lian-shan2; Leng, Ying1
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2014-05 |
| 卷号 | 35期号:5页码:613-624 |
| 关键词 | sodium glucose cotransporter 2 (SGLT2) SHR3824 dapagliflozin type 2 diabetes mellitus blood glucose insulin sensitivity beta-cell function |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2013.196 |
| 文献子类 | Article |
| 英文摘要 | Aim: The sodium glucose cotransporter 2 (SGLT2) plays an important role in renal glucose reabsorption, thus serves as a new target for the treatment of diabetes. The purpose of this study was to evaluate SHR3824 as a novel selective SGLT2 inhibitor and to characterize its in vivo effects on glucose homeostasis. The effects of chronic administration of SHR3824 on peripheral insulin sensitivity and pancreatic beta-cell function were also investigated. Methods: The in vitro potency and selectivity of SHR3824 were assessed in HEK293 cells transfected with human SGLT2 or SGLT1. Acute and multi-dose studies were performed on ICR mice, GK rats and db/db mice to assess the ability of SHR3824 to enhance urinary glucose excretion and improve blood glucose levels. 2-Deoxyglucose uptake and insulin immunohistochemical staining were performed in the soleus muscle and pancreas, respectively, of db/db mice. A selective SGLT2 inhibitor BMS512148 (dapagliflozin) was taken as positive control. Results: SHR3824 potently inhibited human SGLT2 in vitro, but exerted much weak inhibition on human SGLT1 (the IC50 values of SHR3824 against human SGLT2 and SGLT1 were 2.38 and 4324 nmol/L, respectively). Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg.kg(-1).d(-1)) dose-dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice. Conclusion: SHR3824 is a potent and selective SGLT2 inhibitor and exhibits antidiabetic efficacy in several rodent models, suggesting its potential as a new therapeutic agent for the treatment of type 2 diabetes. |
| WOS关键词 | BETA-CELL DIFFERENTIATION ; IMPROVES GLYCEMIC CONTROL ; TYPE-2 DIABETES-MELLITUS ; CHRONIC HYPERGLYCEMIA ; INSULIN-SECRETION ; SGLT-2 INHIBITOR ; SKELETAL-MUSCLE ; RATS ; DAPAGLIFLOZIN ; EMPAGLIFLOZIN |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5142652 |
| WOS记录号 | WOS:000335447000006 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277099]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Leng, Ying |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Shanghai Hengrui Pharmaceut Co Ltd, Shanghai 200245, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yan, Pang-ke,Zhang, Li-na,Feng, Ying,et al. SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models[J]. ACTA PHARMACOLOGICA SINICA,2014,35(5):613-624. |
| APA | Yan, Pang-ke.,Zhang, Li-na.,Feng, Ying.,Qu, Hui.,Qin, Li.,...&Leng, Ying.(2014).SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models.ACTA PHARMACOLOGICA SINICA,35(5),613-624. |
| MLA | Yan, Pang-ke,et al."SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models".ACTA PHARMACOLOGICA SINICA 35.5(2014):613-624. |
入库方式： OAI收割
来源：上海药物研究所
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