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

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. [Display omitted] •A series of ABC type PTP1B inhibitors (P1-P7) were discovered.•P1, P4 and P6 exhibited potent inhibitory activities against PTP1B with IC50 below 1 μM.•P6 exhibited high potent inhibitory activity (IC50 = 50 nM) for PTP1B with 15-fold selectivity over TCPTP.•P6 could enhance insulin-mediated IRβ phosphorylation and insulin-stimulated glucose uptake.