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Structure-Activity Relationships for Substrates and Inhibitors of Mammalian Liver Microsomal Carboxylesterases

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Abstract

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 α-alkyl thioacetothioates were found to be ~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 β or γ 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 α,α′-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 10−9M.

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

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Huang, T.L., Shiotsuki, T., Uematsu, T. et al. Structure-Activity Relationships for Substrates and Inhibitors of Mammalian Liver Microsomal Carboxylesterases. Pharm Res 13, 1495–1500 (1996). https://doi.org/10.1023/A:1016071311190

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  • DOI: https://doi.org/10.1023/A:1016071311190

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