Design and synthesis of novel 1,2-dithiolan-4-yl benzoate derivatives as PTP1B inhibitors

Bioorg Med Chem Lett. 2015;25(10):2211-6. doi: 10.1016/j.bmcl.2015.03.060. Epub 2015 Mar 27.

Abstract

A series of novel 1,2-dithiolan-4-yl benzoate compounds were synthesized and evaluated for in vitro PTP1B inhibitory activity. Some derivatives exhibited improved PTP1B inhibitory activity and selectivity compared to hit 6a, a compound from in-house library screening inspired by marine cyclic disulfide. The preliminary SAR analysis with assistance of molecular modeling approach revealed 6j (IC50=0.59μM) as the most potent PTP1B inhibitor among all derivatives.

Keywords: Diabetes; Disulfide derivative; PTP1B inhibitor; Selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoates / chemical synthesis*
  • Benzoates / chemistry
  • Benzoates / pharmacology*
  • Benzyl Alcohols / chemical synthesis
  • Benzyl Alcohols / chemistry*
  • Benzyl Alcohols / pharmacology
  • Crystallography, X-Ray
  • Drug Delivery Systems
  • Drug Design*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemical synthesis
  • Sulfhydryl Compounds / chemistry*
  • Sulfhydryl Compounds / pharmacology

Substances

  • (thiolan-2-yl)diphenylmethanol
  • Benzoates
  • Benzyl Alcohols
  • Enzyme Inhibitors
  • Sulfhydryl Compounds
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1