Identification of lipid-like salicylic acid-based derivatives as potent and membrane-permeable PTP1B inhibitors

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 P_app = 1.5 × 10⁻⁶ cm/s). We believe that this strategy can be widely utilized to modify potent lead compounds with low cell-permeability.