Toward a treatment of diabesity: In vitro and in vivo evaluation of uncharged bromophenol derivatives as a new series of PTP1B inhibitors
文献类型：期刊论文
| 作者 | Li, Xiangqian1,2; Xu, Qi1; Li, Chao1; Luo, Jiao1; Li, Xiuxue1; Wang, Lijun1,2; Jiang, Bo1,2; Shi, Dayong3 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2019-03-15 |
| 卷号 | 166页码:178-185 |
| 关键词 | Anti-diabetic PTP1B inhibitor Selectivity BKS db mice Toxicity |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2019.01.057 |
| 通讯作者 | Shi, Dayong(shidayong@qdio.ac.cn) |
| 英文摘要 | Protein tyrosine phosphatase 1B (PTP1B) has been considered as a validated biological target for type 2 diabetes treatment, but past endeavors to develop inhibitors of PTP1B into drugs have been unsuccessful. Two challenging aspects are selective inhibition and cell permeability. A structure-based strategy was employed to develop uncharged bromophenols as a new series of PTP1B inhibitors. The most potent compound 22 (LXQ46) inhibited PTP1B with an IC50 value of 0.190 mu M, and showed remarkable selectivity over other protein tyrosine phosphatases (PTPs, 20-200 folds). In the SPR study, increasing concentrations of compound 22 led to concentration-dependent increases in binding responses, indicating that compound 22 could bind to the surface of PTP1B via noncovalent means. By treating insulin resistant C2C12 myotubes with compound 22, enhanced insulin and leptin signaling pathways were observed. Long-term oral administration of compound 22 reduced the blood glucose level of diabetic BKS db mice. The glucose tolerance tests (OGTT) and insulin tolerance tests (ITT) in BKS db mice showed that oral administration of compound 22 could increase insulin sensitivity. In addition, long-term oral administration of compound 22 could protect mice from obesity, which was not the result of toxicity. Our pharmacokinetics results from the rat-based assays showed that orally administered compound 22 was absorbed rapidly from the gastrointestinal tract, extensively distributed to the tissues, and rapidly eliminated from the body. All these results indicate that compound 22 could serve as a qualified agent to treat type II diabetes. (C) 2019 Elsevier Masson SAS. All rights reserved. |
| 资助项目 | National Natural Science Foundation of China[81703354] ; National Natural Science Foundation of China[81773586] ; Key research and development project of Shandong province[2018GSF118200] ; Key research and development project of Shandong province[2016ZDJS07A13] ; NSFC-Shandong Joint Fund[U1706213] ; Key Research Program of Frontier Sciences CAS[QYZDB-SSW-DQC014] ; Aoshan Talents Program ; Qingdao National Laboratory for Marine Science and Technology[2015ASTP] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000461402400016 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://ir.qdio.ac.cn/handle/337002/155265]  |
| 专题 | 海洋研究所_实验海洋生物学重点实验室 |
| 通讯作者 | Shi, Dayong |
| 作者单位 | 1.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, Qingdao, Peoples R China 2.Qingdao Natl Lab Marine Sci & Technol, Lab Marine Drugs & Bioprod, Qingdao, Peoples R China 3.Shandong Univ, State Key Lab Microbial Technol, Qingdao, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Xiangqian,Xu, Qi,Li, Chao,et al. Toward a treatment of diabesity: In vitro and in vivo evaluation of uncharged bromophenol derivatives as a new series of PTP1B inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2019,166:178-185. |
| APA | Li, Xiangqian.,Xu, Qi.,Li, Chao.,Luo, Jiao.,Li, Xiuxue.,...&Shi, Dayong.(2019).Toward a treatment of diabesity: In vitro and in vivo evaluation of uncharged bromophenol derivatives as a new series of PTP1B inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,166,178-185. |
| MLA | Li, Xiangqian,et al."Toward a treatment of diabesity: In vitro and in vivo evaluation of uncharged bromophenol derivatives as a new series of PTP1B inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 166(2019):178-185. |
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来源：海洋研究所
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