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Bioorg Med Chem Lett. 2017 Feb 15;27(4):1105-1108. doi: 10.1016/j.bmcl.2016.11.055. Epub 2016 Nov 22.

Discovery of core-structurally novel PTP1B inhibitors with specific selectivity containing oxindole-fused spirotetrahydrofurochroman by one-pot reaction.

Author information

1
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Rd., Shanghai 200062, China. Electronic address: szdong@brain.ecnu.edu.cn.
2
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Rd., Shanghai 200062, China. Electronic address: leiyubing@163.com.
3
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Rd., Shanghai 200062, China. Electronic address: jiashikun2009@163.com.
4
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China. Electronic address: lxgao@mail.shcnc.ac.cn.
5
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China. Electronic address: jli@mail.shcnc.ac.cn.
6
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Rd., Shanghai 200062, China. Electronic address: tzhu@lps.ecnu.edu.cn.
7
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Rd., Shanghai 200062, China. Electronic address: syliu@sist.ecnu.edu.cn.
8
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Rd., Shanghai 200062, China. Electronic address: whu@chem.ecnu.edu.cn.

Abstract

Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an ideal target for treatment of type II diabetes and obesity. However, no druggable PTP1B inhibitor has been established and there is still an urgent demand for the development of structurally novel PTPIB inhibitor. Herein, we reported core-structurally novel PTP1B inhibitors with low micromole-ranged inhibitory activity by one-pot reaction from simple starting materials. Further studies demonstrated some of these active compounds had a specific selectivity over other PTPs. The structure and activity relationship was also described. The best active and selective compound 5e inhibited PTP1B activity with an IC50 of 4.53μM. Molecular docking analysis further demonstrated that compound 5e bound to the active pocket of PTP1B. The results might provide some insights for further development of new drugs for type II diabetes and obesity.

KEYWORDS:

New structure; Oxindole; PTP1B inhibitor; Polycycle; Spirotetrahydrofurochroman

PMID:
28111140
DOI:
10.1016/j.bmcl.2016.11.055
[Indexed for MEDLINE]

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