1H-2,3-Dihydroperimidine Derivatives: A New Class of Potent Protein Tyrosine Phosphatase 1B Inhibitors

Wen-Long Wang,Jia Li,Jing-Ya Li,Chun-Lan Tang,Ya-Nan Zhao,Li-Xin Gao,Wei-Ping Ma,Zhao Hu,Si-Qi Zhang,Hao-Jie Xu,Hui-Hua Ye,Xia Chen,Wen-Hua Fan,Dong-Lin Yang,Bainian Feng,Hai-Jun Chen,Fa-Jun Nan

doi:10.3390/molecules19010102

Abstract

A series of 1H-2,3-dihydroperimidine derivatives was designed, synthesized, and evaluated as a new class of inhibitors of protein tyrosine phosphatase 1B (PTP1B) with IC50 values in the micromolar range. Compounds 46 and 49 showed submicromolar inhibitory activity against PTP1B, and good selectivity (3.48-fold and 2.10-fold respectively) over T-cell protein tyrosine phosphatases (TCPTP). These results have provided novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

Highlights

Reversible protein tyrosine phosphorylation is a key regulatory mechanism in eukaryotic cell physiology [1]
In addition to potency improvements, we investigated the selectivity of three representative compounds, namely, 1, 46 and 49 against other protein tyrosine phosphatases (PTPs) (TCPTP, SHP-1, SHP-2, LAR)
The results indicated that 46 binds the catalytic pocket of protein tyrosine phosphatase 1B (PTP1B) and behaves as a competitor to the substrate

Summary

Introduction

Reversible protein tyrosine phosphorylation is a key regulatory mechanism in eukaryotic cell physiology [1]. PTKs and PTPs are emerging as high value targets for therapeutic intervention [3,4,5,6,7]. Many efforts have been made to target these enzymes with small molecules in order to develop new therapeutic agents. Notable success has been achieved in targeting signaling pathways regulated by protein tyrosine phosphorylation with more than a dozen of small molecule kinase inhibitors on the market [8]. The therapeutic benefits of modulating PTPs are still underexplored despite the fact that several PTPs have been identified as high value targets [9]

Methods

Results

Conclusion