Developing protein tyrosine phosphatase-1B (PTP1B) inhibitors is an important strategy to treat type 2 diabetes mellitus (T2DM). Most existing ionic PTP1B inhibitors aren't of clinical useful due to their low cell-permeability, however. Herein, we introduced a series of lipid-like acid-based (salicylic acid) modules to prepare PTP1B inhibitors, and demonstrated a marked improvement of cell-permeability while maintaining excellent PTP1B inhibitory activity (e.g. compound B12D, IC50 = 0.37 μM against PTP1B and Papp = 1.5 × 10-6 cm/s). We believe that this strategy can be widely utilized to modify potent lead compounds with low cell-permeability.
Keywords: Membrane permeability; PTP1B inhibitors; Salicylic acid-based derivatives; T2DM.
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