Function of Esterases

Non-specific esterases are distributed widely throughout the body. The activity of these enzymes varies markedly within different tissues. In mammals the highest levels are found in liver and kidney. Numerous isoenzymes exist which have broad substrate overlap. A loose categorization divides the two enzyme types likely to be involved in drug hydrolysis into arylesterases and aliesterases. Aliesterases have a wide substrate range, arylesterases require a phenolic ester. Since most of the major tissues contain a mixture this division is not of great importance. Where esters are of great benefit to drug design is in the design of rapidly cleared molecules, either to an inactive or active form. The most rapid clearance is by blood metabolism. An important point in the screening of compounds designed for rapid metabolism is that the erythrocyte surface has a high esterase content and whole blood is therefore the medium of choice. Moreover rodent blood has very high esterase levels, and may

Fig. 7.17 Proposed mechanism for non-specific esterase catalysis involving a serine residue.

give a misleading view of stability if this species is used in isolation. It is highly likely that many of these enzymes are serine esterases and a suggested mechanism is proposed in Figure 7.17.

Ester functions present in molecules tend to be considered labile although steric effects etc. may be utilized to produce drugs without inherent chemical or metabolic problems due to ester lability. For instance a series of antimuscarinic compounds which had selectivity for the M3 receptor (Figure 7.18) were stabilized by the incorporation of a hydroxyethyl side chain or a cyclic ring system at positions surrounding the ester function. Presumably the proximity of these groups to the ester function (carbonyl) prevents close approach of the "attacking" nucleophile, in this case probably a serine hydroxyl.

Fig. 7.18 Stabilization of antimuscarinic compounds to esterase activity by steric effects. Stability was achieved when groupings corresponding to those illustrated were incorporated.

88 | 7 Metabolic (Hepatic) Clearance 7.4.2

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