Discovery of novel and potent heterocyclic carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2843-9. doi: 10.1016/j.bmcl.2012.02.070. Epub 2012 Mar 1.

Abstract

A series of novel heterocyclic carboxylic acid based protein tyrosine phosphatase 1B (PTP1B) inhibitors with hydrophobic tail have been synthesized and characterized. Structure-activity relationship (SAR) optimization resulted in identification of several potent, selective (over the highly homologous T-cell protein tyrosine phosphatase, TCPTP) and metabolically stable PTP1B inhibitors. Compounds 7a, 19a and 19c showed favorable cell permeability and pharmacokinetic properties in mouse with moderate to very good oral (% F=13-70) bio-availability.

MeSH terms

  • Administration, Oral
  • Animals
  • Carboxylic Acids / chemical synthesis*
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology
  • Hydrophobic and Hydrophilic Interactions
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Carboxylic Acids
  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1