Potent, selective inhibitors of protein tyrosine phosphatase 1B

Bioorg Med Chem Lett. 2003 Jun 2;13(11):1887-90. doi: 10.1016/s0960-894x(03)00302-0.

Abstract

We have previously reported a novel series of oxalyl-aryl-amino benzoic acid-based, catalytic site-directed, competitive, reversible protein tyrosine phosphatase 1B (PTP1B) inhibitors. With readily access to key intermediates, we utilized a solution phase parallel synthesis approach and rapidly identified a highly potent PTP1B inhibitor (19, K(i)=76 nM) with moderate selectivity (5-fold) over T-cell PTPase (TCPTP) through interacting with a second phosphotyrosine binding site (site 2) in the close proximity to the catalytic site.

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology
  • Benzoates / chemistry*
  • Benzoates / pharmacology*
  • Binding Sites
  • Catalytic Domain
  • Combinatorial Chemistry Techniques
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Ligands
  • Molecular Structure
  • Phosphotyrosine / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Structure-Activity Relationship
  • T-Lymphocytes / enzymology

Substances

  • Amides
  • Benzoates
  • Enzyme Inhibitors
  • Ligands
  • Phosphotyrosine
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases