Y-shaped bis-arylethenesulfonic acid esters: Potential potent and membrane permeable protein tyrosine phosphatase 1B inhibitors

Bioorg Med Chem Lett. 2017 May 15;27(10):2166-2170. doi: 10.1016/j.bmcl.2017.03.060. Epub 2017 Mar 23.

Abstract

Known PTP1B inhibitors with bis-anionic moieties exhibit potent inhibitory activity, good selectivity, however, they are incapable of penetrating cellular membranes. Based upon our finding of a new pharmacophoric group in inhibition of PTP1B and the structural characteristics of the binding pocket of PTP1B, a series of bis-arylethenesulfonic acid ester derivatives were designed and synthesized. These novel molecules, particularly Y-shaped bis-arylethenesulfonic acid ester derivatives, exhibited high PTP1B inhibitory activity, moderate selectivity, and great potential in penetrating cellular membranes (compound 7p, CLogP=9.73, Papp=9.6×10-6cm/s; IC50=140, 1290 and 920nM on PTP1B, TCPTP and SHP2, respectively). Docking simulations suggested that these Y-shaped inhibitors might interact with multiple secondary binding sites in addition to the catalytic site of PTP1B.

Keywords: Arylethenesulfonic acid esters; PTP1B inhibitors; Phosphotyrosine mimics; Type 2 diabetes.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Esters / chemistry*
  • Inhibitory Concentration 50
  • Lipid Bilayers / chemistry
  • Lipid Bilayers / metabolism
  • Permeability / drug effects
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Structure-Activity Relationship
  • Sulfonic Acids / chemical synthesis
  • Sulfonic Acids / chemistry*
  • Sulfonic Acids / pharmacology

Substances

  • Enzyme Inhibitors
  • Esters
  • Lipid Bilayers
  • Sulfonic Acids
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1