Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors

Bioorg Med Chem Lett. 2019 May 15;29(10):1187-1193. doi: 10.1016/j.bmcl.2019.03.023. Epub 2019 Mar 20.

Abstract

Two series of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, IIIv was found to have the best in vitro inhibition activity against PTP1B (IC50 = 0.67 ± 0.09 µM) and the best selectivity (9-fold) between PTP1B and T-cell protein tyrosine phosphatase (TCPTP). Molecular docking studies demonstrated that compounds IIIm, IIIv and IVg could occupy simultaneously at both the catalytic site and the adjacent pTyr binding site. These results provide novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

Keywords: 1,3-Diphenyl-1H-pyrazole; PTP1B inhibitor; Rhodanine-3-alkanoic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Biphenyl Compounds / chemistry
  • Catalytic Domain
  • Drug Design*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Humans
  • Kinetics
  • Molecular Docking Simulation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism
  • Rhodanine / chemistry*
  • Structure-Activity Relationship

Substances

  • Biphenyl Compounds
  • Enzyme Inhibitors
  • Pyrazoles
  • diphenyl
  • Rhodanine
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1