Discovery of novel, potent, selective and cellular active ADC type PTP1B inhibitors via fragment-docking-oriented de novel design

Bioorg Med Chem. 2015 Aug 1;23(15):4891-4898. doi: 10.1016/j.bmc.2015.05.032. Epub 2015 Jun 9.

Abstract

Fragment-docking-oriented de novel design for both the catalytic site and the C phosphotyrosine binding site led to the discovery of novel scaffold and chemical easy N-(2,5-diethoxy-phenyl)-methanesulfonamide based phosphotyrosine mimetics that when incorporated into ureas are high potent and selective inhibitors of protein tyrosine phosphatase 1B. Among them, compound 15 was shown to be the most potent PTP1B inhibitor with great selectivity over the highly homologous T-cell protein tyrosine phosphatase.

Keywords: Insulin signaling; N-(2,5-Diethoxy-phenyl)-methanesulfonamide; Protein tyrosine phosphatase 1B inhibitor; Type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Humans
  • Kinetics
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism

Substances

  • Enzyme Inhibitors
  • Sulfonamides
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1