Ester and amide derivatives of E64c as inhibitors of platelet calpains

J Med Chem. 1992 May 29;35(11):2048-54. doi: 10.1021/jm00089a015.


Ester and amide derivatives of E64c, (+)-(2S,3S)-3-[[(S)-3-methyl-1- [(3-methylbutyl)carbamoyl]butyl]carbamoyl]-2-oxiranecarboxylic acid, an inhibitor of calpains, were synthesized and tested for ability to inhibit calpain in lysed cells, ability to enter intact cells, and ability to inhibit calpain in intact cells. The esters were from halogen-substituted alcohols and alcohols with increasing size. There were no appreciable differences in the inhibitory potency of any of the halogen-substituted esters from ethyl to trifluoroethyl, indicating that ease of hydrolysis of this class of ester is not important for activity. The only ester with impaired activity was the largest, Z-leucyl-norleucyl, which was about 5% as effective as the ethyl ester, E64d. Amides of amino acid esters also had impaired activity. To explore the possibility of targeting E64c derivatives to specific cells, esters and amides of E64c with 5-hydroxytryptamine were tested on the rationale that the active 5-hydroxytryptamine uptake mechanism of platelets might selectively concentrate the drug in platelets. Both the ester and amide inhibited calpain in lysed cells, but only the ester inhibited in intact cells. The 5-hydroxytryptamine ester showed no advantage over the ethyl ester in entering platelets.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Blood Platelets / drug effects
  • Blood Platelets / enzymology*
  • Blood Platelets / metabolism
  • Calcimycin / pharmacology
  • Calcium / pharmacology
  • Calpain / antagonists & inhibitors*
  • Cysteine Proteinase Inhibitors / chemical synthesis*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Esters / pharmacology
  • Humans
  • Leucine / analogs & derivatives*
  • Leucine / chemistry
  • Leucine / pharmacology
  • Serotonin / blood
  • Structure-Activity Relationship


  • Cysteine Proteinase Inhibitors
  • Esters
  • Serotonin
  • Calcimycin
  • N-(N-(3-carboxyoxirane-2-carbonyl)leucyl)isoamylamine
  • Calpain
  • Leucine
  • Calcium