The development of potent non-peptidic PTP-1B inhibitors

Bioorg Med Chem Lett. 2004 Feb 23;14(4):1039-42. doi: 10.1016/j.bmcl.2003.11.048.

Abstract

The SAR from our peptide libraries was exploited to design a series of potent deoxybenzoin PTP-1B inhibitors. The introduction of an ortho bromo substituent next to the difluoromethylphosphonate warhead gave up to 20-fold increase in potency compared to the desbromo analogues. In addition, these compounds were orally bioavailable and active in the animal models of non-insulin dependent diabetes mellitus (NIDDM).

MeSH terms

  • Administration, Oral
  • Animals
  • Benzoin / analogs & derivatives
  • Benzoin / chemical synthesis
  • Benzoin / pharmacology*
  • Biological Availability
  • Cell Line
  • Cell Survival / drug effects
  • Diabetes Mellitus / enzymology
  • Diabetes Mellitus / metabolism
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Insecta
  • Mice
  • Mice, Knockout
  • Models, Animal
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases
  • Ptpn1 protein, mouse
  • Benzoin