Discovery of novel high potent and cellular active ADC type PTP1B inhibitors with selectivity over TC-PTP via modification interacting with C site

Eur J Med Chem. 2018 Jan 20:144:692-700. doi: 10.1016/j.ejmech.2017.12.064. Epub 2017 Dec 20.

Abstract

PTP1B serving as a key negative regulator of insulin signaling is a novel target for type 2 diabetes and obesity. Modification at ring B of N-{4-[(3-Phenyl-ureido)-methyl]-phenyl}-methane-sulfonamide template to interact with residues Arg47 and Lys41 in the C site of PTP1B by molecular docking aided design resulted in the discovery of a series of novel high potent and selective inhibitors of PTP1B. The structure activity relationship interacting with the C site of PTP1B was well illustrated. Compounds 8 and 18 were shown to be the high potent and most promising PTP1B inhibitors with cellular activity and great selectivity over the highly homologous TCPTP and other PTPs.

Keywords: N-(2,5-diethoxy-phenyl)-methane sulfonamide; PTP1B; Protein tyrosine phosphatase 1B inhibitors; Type 2 diabetes mellitus.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2