Design and synthesis of novel metalloproteinase inhibitors

Bioorg Med Chem. 2006 Aug 1;14(15):5402-22. doi: 10.1016/j.bmc.2006.03.032. Epub 2006 Apr 18.

Abstract

A series of N-benzoyl 4-aminobutyric acid hydroxamate analogs were synthesized and evaluated as matrix metalloproteinase inhibitors. Synthetic work was focused on the chemical modification of the 4-aminobutyric acid part using easily available starting materials. As such, chemical modification was carried out using commercially available starting materials such as 4-aminobutyric acid, (+)- and (-)-malic acid, and D- and L-glutamic acid derivatives. Among the compounds tested, N-[4-(benzofuran-2-yl)benzoyl] 4-amino-4S-hydroxymethylbutyric acid hydroxamates derived from L-glutamic acid demonstrated more potent inhibitory activity against MMP-2 and MMP-9 compared with the corresponding 2S-hydroxy analogs or 3S-hydroxy analogs, respectively, which were derived from (-)-malic acid. Structure-activity relationship study is presented.

MeSH terms

  • Benzofurans* / chemical synthesis
  • Benzofurans* / chemistry
  • Benzofurans* / pharmacology
  • Butyrates* / chemical synthesis
  • Butyrates* / chemistry
  • Butyrates* / pharmacology
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Humans
  • Matrix Metalloproteinase Inhibitors*
  • Molecular Structure
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tissue Inhibitor of Metalloproteinases* / chemical synthesis
  • Tissue Inhibitor of Metalloproteinases* / chemistry
  • Tissue Inhibitor of Metalloproteinases* / pharmacology

Substances

  • Benzofurans
  • Butyrates
  • Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • N-(4-(benzofuran-2-yl)benzoyl)4-amino-4S-hydroxymethylbutyric acid
  • Tissue Inhibitor of Metalloproteinases