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Toward a treatment of diabesity: In vitro and in vivo evaluation of uncharged bromophenol derivatives as a new series of PTP1B inhibitors
Li, Xiangqian1,2; Xu, Qi1; Li, Chao1; Luo, Jiao1; Li, Xiuxue1; Wang, Lijun1,2; Jiang, Bo1,2; Shi, Dayong3
2019-03-15
Source PublicationEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN0223-5234
Volume166Pages:178-185
Corresponding AuthorShi, Dayong(shidayong@qdio.ac.cn)
AbstractProtein 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.
KeywordAnti-diabetic PTP1B inhibitor Selectivity BKS db mice Toxicity
DOI10.1016/j.ejmech.2019.01.057
Indexed BySCI
Language英语
Funding ProjectNational 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 Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000461402400016
PublisherELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.qdio.ac.cn/handle/337002/155265
Collection实验海洋生物学重点实验室
Corresponding AuthorShi, Dayong
Affiliation1.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
First Author AffilicationInstitute of Oceanology, Chinese Academy of Sciences
Recommended Citation
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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