Discovery of 5-(3-bromo-2-(2,3-dibromo-4,5-dimethoxybenzyl)-4,5-dimethoxybenzylidene)thiazolidine-2,4-dione as a novel potent protein tyrosine phosphatase 1B inhibitor with antidiabetic properties.

Protein tyrosine phosphatase 1B (PTP1B) is a well-validated target in therapeutic interventions for type 2 diabetes mellitus (T2DM), however, PTP1B inhibitors containing negatively charged nonhydrolyzable pTyr mimetics are difficult to convert to the corresponding in vivo efficacy owing to poor cell permeability and oral bioavailability. In this work, molecules bearing less acidic heterocycle 2,4-thiazolidinedione and hydantoin were designed, synthesized and evaluated for PTP1B inhibitory potency, selectivity and in vivo antidiabetic efficacy. Among them, compound 5a was identified as a potent PTP1B inhibitor (IC = 0.86 μM) with 5-fold selectivity over the highly homologous TCPTP. Long-term oral administration of 5a at a dose of 50 mg/kg not only significantly reduced blood glucose levels, triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) levels but also ameliorated insulin sensitivity in diabetic BKS db mice. Moreover, 5a enhanced the insulin-stimulated phosphorylation of IRβ, IRS-1 and Akt in C2C12 myotubes. A histopathological evaluation of liver and pancreas demonstrated that 5a increased liver glycogen storage and improved islet architecture with more β-cells and fewer α-cells in diabetic mice. Thus, our work demonstrated that compound 5a could serve as a lead compound for the discovery of new antidiabetic drugs.