Structure-activity relationship study and drug profile of N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal (SJA6017) as a potent calpain inhibitor

J Med Chem. 2003 Feb 27;46(5):868-71. doi: 10.1021/jm0201924.

Abstract

Novel N-arylsulfonyldipeptidyl aldehyde derivatives were prepared by DMSO oxidation from the corresponding dipeptide alcohol, and their potencies as calpain inhibitors were evaluated in vitro. Among them, N-(4-fluorophenylsulfonyl)-l-valyl-l-leucinal (8, SJA6017) potently inhibited calpains. 8 also inhibited cathepsin B and L but did not inhibit other cysteine proteases (interleukin 1beta-converting enzyme), serine proteases (trypsin, chymotrypsin, thrombin, factor VIIa, factor Xa), or proteasome. Preliminary cytotoxicity studies of 8 exhibited a relatively safe profile.

MeSH terms

  • Animals
  • Blood Proteins / metabolism
  • Caco-2 Cells
  • Calpain / antagonists & inhibitors*
  • Cells, Cultured
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Dipeptides / pharmacology
  • Dogs
  • Haplorhini
  • Hepatocytes / enzymology
  • Humans
  • In Vitro Techniques
  • Mice
  • Microsomes / metabolism
  • Permeability
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / toxicity
  • Rats
  • Species Specificity
  • Structure-Activity Relationship
  • Toxicity Tests, Acute
  • Toxicity Tests, Chronic

Substances

  • Blood Proteins
  • Dipeptides
  • N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal
  • Protease Inhibitors
  • Cytochrome P-450 Enzyme System
  • Calpain