STRUCTURE-ACTIVITY-RELATIONSHIPS FOR SUBSTRATES AND INHIBITORS OF MAMMALIAN LIVER MICROSOMAL CARBOXYLESTERASES

Purpose. Carboxylesterases are important in the detoxification of drug s, pesticides and other xenobiotics. This study was to evaluate a seri es of substrates and inhibitors for characterizing these enzymes. Meth ods. A series of novel aliphatic esters and thioesters were used in sp ectral assays to monitor human, murine and porcine esterases. A series of transition state mimics were evaluated as selective esterase inhib itors. Results. Several alpha-alkyl thioacetothioates were found to be similar to 2 to 11-fold superior to commonly used substrates for moni toring carboxylesterase activity. Insertion of a heteroatom in the aci d portion of these esters in the beta or gamma position relative to th e carbonyl had a dramatic effect on enzyme activity with S or O substi tuents often improving the k(CAT)/K-M ratio of the substrate and PI de creasing it. Several ha,alpha'-(2-oxo-3,3,3-trifluoropropylthio(alkane s proved to be potent selective transition state mimics of the esteras e activity with IC50's from 10(-5) to 10(-9) M. Conclusions. This libr ary of substrates and inhibitors are useful research tools for charact erizing the numerous isozymes of carboxylesterases present in mammalia n tissues.