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.
Peihong Liu  1 ,  Yongli Du  2 ,  Lianhua Song  1 ,  Jingkang Shen  3 ,  Qunyi Li  4
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: [email protected].
  • 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: [email protected].
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.
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