Carboxylesterase inhibitors

Abstract

Introduction: Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis.

Areas covered: This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors.

Expert opinion: The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties and potential uses of such agents are discussed here.

Figure 1

Carboxylesterase substrates. The site(s) of enzymatic cleavage is(are) indicated by the arrow(s).

Figure 2

Chemical structures of carboxylesterase inhibitors.

Figure 3

Proposed mechanism of CE inhibition by benzil. The essential catalytic residues in CEs (Ser, His and Glu) are depicted, and the upper half of the figure demonstrates the initial steps in the hydrolysis of an ester (RCOOR₁). The serine nucleophile attacks the carbonyl carbon atom to yield a tetrahedral complex that collapses (cleavage of green C–O bond) to release the alcohol and generate a serine ester. When the enzyme interacts with benzil (lower half of the figure), it is presumed that the same attack occurs, but now the complex cannot degrade since the C–O bond is now replaced by the stronger C–C bond (red). Due to the lack of polarization and increased strength of the latter, cleavage does not occur. Hence, an equilibrium is likely established between the enzyme, and free and complexed inhibitor, that essential results in an inactivation of the protein. Adapted from [23] with permission.

Figure 4

Organophosphate and carbamate inhibitors of carboxylesterases