Protein tyrosine phosphatase 1B (PTP1B) plays an important role in the negative regulation of insulin and leptin signaling. The development of small molecular inhibitors targeting PTP1B has been validated as a potential therapeutic strategy for Type 2 diabetes (T2D). In this work, we have identified a series of compounds containing dihydropyridine thione and particular chiral structure as novel PTP1B inhibitors. Among those, compound 4b showed moderate activity with IC value of 3.33 μM and meanwhile with good selectivity (>30-fold) against TCPTP. The further MOA study of PTP1B demonstrated that compounds 4b is a substrate-competitive inhibitor. The binding mode analysis suggested that compound 4b simultaneously occupies the active site and the second phosphotyrosine (pTyr) binding site of PTP1B. Furthermore, the cell viability assay of compound 4b showed tolerable cytotoxicity in L02 cells, thus 4b may be prospectively used to further in vivo study.
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