Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B

Bioorg Med Chem Lett. 2012 Dec 1;22(23):7237-42. doi: 10.1016/j.bmcl.2012.09.040. Epub 2012 Sep 21.

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both insulin and leptin signals. For years, inhibiting of PTP1B has been considered to be a potential therapeutics for treating Type 2 diabetes and obesity. Recently, we recognized lithocholic acid (LCA) as a natural inhibitor against PTP1B (IC(50)=12.74 μM) by a vertical screen for the first time. Further SAR research was carried out by synthesizing and evaluating a series of compounds bearing two methyls at C-4 position and a fused heterocycle to ring A. Among them, compound 14b achieved a PTP1B inhibitory activity about eightfold than LCA and a 14-fold selectivity over the homogenous enzyme TCPTP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Diabetes Mellitus, Type 2 / drug therapy
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Kinetics
  • Lithocholic Acid / analogs & derivatives*
  • Lithocholic Acid / chemical synthesis
  • Lithocholic Acid / chemistry
  • Lithocholic Acid / therapeutic use
  • Molecular Docking Simulation
  • Obesity / drug therapy
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Structure-Activity Relationship

Substances

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