New type of metalloproteinase inhibitor: design and synthesis of new phosphonamide-based hydroxamic acids

J Med Chem. 2002 Feb 14;45(4):919-29. doi: 10.1021/jm0103211.

Abstract

A series of phosphonamide-based hydroxamate derivatives were synthesized, and the inhibitory activities were evaluated against various metalloproteinases in order to clarify its selectivity profile. Among the four diastereomeric isomers resulting from the chirality at the C-3 and P atoms, the compound with a (R,R)-configuration both at the C-3 position and the phosphorus atom was found to be potently active, while the other diastereomeric isomers were almost inactive. A number of (R,R)-compounds synthesized here exhibited broad spectrum activities with nanomolar K(i) values against MMP-1, -3, -9, and TACE and also showed nanomolar IC(50) values against HB-EGF shedding in a cell-based inhibition assay. The modeling study using X-ray structure of MMP-3 suggested the possible binding mode of the phosphonamide-based inhibitors.

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Crystallography, X-Ray
  • Epidermal Growth Factor / antagonists & inhibitors
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • Intercellular Signaling Peptides and Proteins
  • Matrix Metalloproteinase 1 / chemistry
  • Matrix Metalloproteinase 3 / chemistry
  • Matrix Metalloproteinase 9 / chemistry
  • Matrix Metalloproteinase Inhibitors
  • Metalloendopeptidases / antagonists & inhibitors*
  • Metalloendopeptidases / chemistry
  • Models, Molecular
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Protein Binding
  • Recombinant Proteins / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Amides
  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • Hydroxamic Acids
  • Intercellular Signaling Peptides and Proteins
  • Matrix Metalloproteinase Inhibitors
  • Organophosphonates
  • Protease Inhibitors
  • Recombinant Proteins
  • Epidermal Growth Factor
  • Metalloendopeptidases
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 1