title: Discovery of core-structurally novel PTP1B inhibitors with specific selectivity containing oxindole-fused spirotetrahydrofurochroman by one-pot reaction.
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 IC50of 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.
authors.affiliation: 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.
authors.forename: Suzhen
authors.initials: S
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: Yubing
authors.initials: Y
authors.lastname: Lei
authors.affiliation: 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.
authors.forename: Shikun
authors.initials: S
authors.lastname: Jia
authors.affiliation: 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.
authors.forename: Lixin
authors.initials: L
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Shunying
authors.initials: S
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Hu
mesh_terms: D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D000078183:Oxindoles; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D000078183:Oxindoles; C022960:2-oxindole; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: New structure; Oxindole; PTP1B inhibitor; Polycycle; Spirotetrahydrofurochroman