New non-hydroxamic ADAMTS-5 inhibitors based on the 1,2,4-triazole-3-thiol scaffold

Bioorg Med Chem Lett. 2010 Nov 1;20(21):6213-6. doi: 10.1016/j.bmcl.2010.08.108. Epub 2010 Aug 27.

Abstract

In this Letter we describe the design, synthesis, screening, and optimization of a new family of ADAMTS-5 inhibitors. These inhibitors display an original 1,2,4-triazole-3-thiol scaffold as a putative zinc binding-group. In vitro results are rationalized by in silico docking of the compounds in ADAMTS-5's crystal structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAMTS5 Protein
  • Binding Sites
  • Computer Simulation
  • Drug Evaluation, Preclinical
  • Humans
  • Indicators and Reagents
  • Models, Molecular
  • Osteoarthritis / drug therapy
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Protein Binding
  • Protein Conformation
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacology*
  • X-Ray Diffraction

Substances

  • Indicators and Reagents
  • Protease Inhibitors
  • Triazoles
  • ADAM Proteins
  • ADAMTS5 Protein
  • ADAMTS5 protein, human