Structure-activity relationships for substrates and inhibitors of mammalian liver microsomal carboxylesterases

Pharm Res. 1996 Oct;13(10):1495-500. doi: 10.1023/a:1016071311190.


Purpose: Carboxylesterases are important in the detoxification of drugs, pesticides and other xenobiotics. This study was to evaluate a series of substrates and inhibitors for characterizing these enzymes.

Methods: A series of novel aliphatic esters and thioesters were used in spectral assays to monitor human, murine and porcine esterases. A series of transition state mimics were evaluated as selective esterase inhibitors.

Results: Several alpha-alkyl thioacetothioates were found to be approximately 2 to 11-fold superior to commonly used substrates for monitoring carboxylesterase activity. Insertion of a heteroatom in the acid portion of these esters in the beta or gamma position relative to the carbonyl had a dramatic effect on enzyme activity with S or O substituents often improving the kCAT/K(M) ratio of the substrate and N decreasing it. Several alpha,alpha'-bis (2-oxo-3,3,3-trifluoropropylthio)alkanes proved to be potent selective transition state mimics of the esterase activity with IC50's from 10(-5) to 10(-9)M.

Conclusions: This library of substrates and inhibitors are useful research tools for characterizing the numerous isozymes of carboxylesterases present in mammalian tissues.

Publication types

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

MeSH terms

  • Animals
  • Carboxylic Ester Hydrolases / antagonists & inhibitors*
  • Carboxylic Ester Hydrolases / metabolism*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydrocarbons, Fluorinated / metabolism
  • Hydrocarbons, Fluorinated / pharmacology*
  • Hydrogen-Ion Concentration
  • Kinetics
  • Mice
  • Microsomes, Liver / enzymology*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Swine


  • Enzyme Inhibitors
  • Hydrocarbons, Fluorinated
  • Carboxylic Ester Hydrolases