Toward a treatment of diabesity: In vitro and in vivo evaluation of uncharged bromophenol derivatives as a new series of PTP1B inhibitors

doi:10.1016/j.ejmech.2019.01.057

IOCAS-IR > 实验海洋生物学重点实验室

	Toward a treatment of diabesity: In vitro and in vivo evaluation of uncharged bromophenol derivatives as a new series of PTP1B inhibitors
	Li, Xiangqian 1,2; Xu, Qi 1; Li, Chao 1; Luo, Jiao 1; Li, Xiuxue 1; Wang, Lijun 1,2; Jiang, Bo 1,2; Shi, Dayong 3
	2019-03-15
发表期刊	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN	0223-5234
卷号	166 页码:178-185
通讯作者	Shi, Dayong(shidayong@qdio.ac.cn)
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.
关键词	Anti-diabetic PTP1B inhibitor Selectivity BKS db mice Toxicity
DOI	10.1016/j.ejmech.2019.01.057
收录类别	SCI
语种	英语
资助项目	Qingdao National Laboratory for Marine Science and Technology[2015ASTP] ; Aoshan Talents Program ; Key Research Program of Frontier Sciences CAS[QYZDB-SSW-DQC014] ; NSFC-Shandong Joint Fund[U1706213] ; Key research and development project of Shandong province[2016ZDJS07A13] ; Key research and development project of Shandong province[2018GSF118200] ; National Natural Science Foundation of China[81773586] ; National Natural Science Foundation of China[81703354] ; 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
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000461402400016
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
引用统计	被引频次：21[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.qdio.ac.cn/handle/337002/155265
专题	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
第一作者单位	中国科学院海洋研究所
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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