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

Bioorg Chem. 2019 Dec:93:103296. doi: 10.1016/j.bioorg.2019.103296. Epub 2019 Sep 17.

Abstract

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.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Cell Membrane Permeability / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Lipids / chemistry*
  • Molecular Docking Simulation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Salicylic Acid / chemistry*
  • Salicylic Acid / metabolism
  • Salicylic Acid / pharmacology
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Lipids
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Salicylic Acid