Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis

Bioorg Med Chem Lett. 2010 Jan 15;20(2):576-80. doi: 10.1016/j.bmcl.2009.11.081. Epub 2009 Nov 22.

Abstract

Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Cartilage / drug effects
  • Cartilage / metabolism
  • Catalytic Domain
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Discovery
  • Matrix Metalloproteinase 13 / metabolism
  • Matrix Metalloproteinase Inhibitors*
  • Osteoarthritis / drug therapy*
  • Picolinic Acids / chemical synthesis
  • Picolinic Acids / chemistry*
  • Picolinic Acids / pharmacology
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Rats
  • Tetrazoles / chemical synthesis
  • Tetrazoles / chemistry*
  • Tetrazoles / pharmacology
  • Zinc / chemistry

Substances

  • Matrix Metalloproteinase Inhibitors
  • Picolinic Acids
  • Protease Inhibitors
  • Tetrazoles
  • Matrix Metalloproteinase 13
  • Zinc