Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors

Bioorg Med Chem Lett. 2002 May 20;12(10):1387-90. doi: 10.1016/s0960-894x(02)00183-x.


A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood.

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Kinetics
  • Metalloendopeptidases / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Conformation
  • Pipecolic Acids / chemical synthesis*
  • Pipecolic Acids / chemistry
  • Pipecolic Acids / pharmacology
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology


  • Enzyme Inhibitors
  • Pipecolic Acids
  • Sulfonamides
  • ADAM Proteins
  • Metalloendopeptidases
  • ADAM17 Protein
  • ADAM17 protein, human