Discovery of novel, high potent, ABC type PTP1B inhibitors with TCPTP selectivity and cellular activity

Peihong Liu; Yongli Du; Lianhua Song; Jingkang Shen; Qunyi Li

doi:10.1016/j.ejmech.2016.04.014

Discovery of novel, high potent, ABC type PTP1B inhibitors with TCPTP selectivity and cellular activity

Eur J Med Chem. 2016 Aug 8:118:27-33. doi: 10.1016/j.ejmech.2016.04.014. Epub 2016 Apr 9.

Authors

Peihong Liu¹, Yongli Du², Lianhua Song¹, Jingkang Shen³, Qunyi Li⁴

Affiliations

¹ School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, 3501 Daxue Road, Jinan 250353, China.
² School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, 3501 Daxue Road, Jinan 250353, China. Electronic address: ylduyjs@163.com.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
⁴ Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, 12 Wu Lu Mu Qi M Road, Shanghai 200040, China. Electronic address: qyli1234@163.com.

PMID: 27123900
DOI: 10.1016/j.ejmech.2016.04.014

Abstract

Protein tyrosine phosphatase 1B (PTP1B) as a key negative regulator of both insulin and leptin receptor pathways has been an attractive therapeutic target for the treatment of type 2 diabetes mellitus (T2DM) and obesity. With the goal of enhancing potency and selectivity of the PTP1B inhibitors, a series of methyl salicylate derivatives as ABC type PTP1B inhibitors (P1-P7) were discovered. More importantly, compound P6 exhibited high potent inhibitory activity (IC50 = 50 nM) for PTP1B with 15-fold selectivity over T-cell PTPase (TCPTP). Further studies on cellular activities revealed that compound P6 could enhance insulin-mediated insulin receptor β (IRβ) phosphorylation and insulin-stimulated glucose uptake.

Keywords: ABC type PTP1B inhibitor; Methyl salicylate derivatives; Type 2 diabetes mellitus.

MeSH terms

Animals
CHO Cells
Cricetinae
Cricetulus
Drug Design*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Glucose / metabolism
Humans
Molecular Docking Simulation
Protein Conformation
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / chemistry
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism*
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
Structure-Activity Relationship
Substrate Specificity

Substances

Enzyme Inhibitors
PTPN11 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein Tyrosine Phosphatase, Non-Receptor Type 2
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Glucose