Guanidinophenyl-substituted enol lactones as selective, mechanism-based inhibitors of trypsin-like serine proteases

J Med Chem. 1992 Oct 30;35(22):4150-9. doi: 10.1021/jm00100a021.


We have synthesized four guanidinophenyl-substituted protio enol and iodo enol lactones (3-(4-guanidinophenyl)-6-methylidenetetrahydro-2-pyranone (1), 3-(4-guanidinophenyl)-6-(E)-(iodomethylidene)tetrahydro-2-pyran one (2), 4-(4-guanidinophenyl)-6-methylidenetetrahydro-2-pyranone+ ++ (3), and 4-(4-guanidinophenyl)-6-(E)-(iodomethylidene)tetrahydro-2-pyran one (4)) and tested them for inhibitory activity against some trypsin-like enzymes, namely trypsin, urokinase, tissue plasminogen activator (t-PA), plasmin, and thrombin, as well as alpha-chymotrypsin and human neutrophil elastase (HNE). The beta-aryl-substituted protio lactone 3 was a potent alternate substrate inhibitor of trypsin and urokinase. The alpha-aryl-substituted iodo lactone 2 was a permanent inactivator of urokinase, plasmin, t-PA, thrombin, and alpha-chymotrypsin, exhibiting a relatively high specificity for the former two enzymes. In general, these compounds showed a preference for inactivating trypsin-like enzymes over alpha-chymotrypsin and HNE. Also, within the class of trypsin-like enzymes, there was generally good selectivity of inhibition.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Guanidines / chemical synthesis
  • Guanidines / pharmacology
  • Kinetics
  • Lactones / chemical synthesis*
  • Lactones / pharmacology
  • Models, Chemical
  • Molecular Sequence Data
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / pharmacology
  • Structure-Activity Relationship


  • Guanidines
  • Lactones
  • Serine Proteinase Inhibitors