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.

Molecular Basis of Valine-Citrulline-PABC Linker Instability in Site-Specific ADCs and Its Mitigation by Linker Design

“…1B). Proteomic analysis of the active fraction identified mouse Carboxylesterases 1C and 1G (Ces1C and Ces1G) among the top candidates, both capable of hydrolyzing amide bonds, and both potentially sensitive to the serine hydrolase inhibitors Pefabloc and BNPP (22). To determine whether Ces1C, Ces1G, or both enzymes can cleave the VC-PABC-based linkers, the activity of commercially available mouse Ces1C and Ces1G, expressed recombinantly from yeast and a mouse myeloma cell line, respectively, was tested with the C16 Site A-C6-VC-PABC-Aur0101 substrate.…”

Carboxylesterase 1 as a Determinant of Clopidogrel Metabolism and Activation

“…Data recently generated in our laboratory and by others demonstrate that the expression of CES1 is markedly lower in neonates and infants, and gradually increases in a developmental manner; full maturation in expression and function is observed by age 6 to 9 years (Yang et al, 2009;Zhu et al, 2009a;Shi et al, 2011). Additionally, a number of commonly used medications have been recently identified as CES1 inhibitors or inducers Fukami et al, 2010;Zhu et al, 2010;Hatfield and Potter, 2011;Rhoades et al, 2012). However, the magnitude of the effects and the clinical significance of CES1 inhibitors/inducers and developmental age need to be validated by in vivo assessments, and both areas of study are in their relative infancy.…”

P-Glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain and Blood Disposition of the mTOR Inhibitor Everolimus (Afinitor) in Mice

“…However, inhibition of the hepatic CES1 and especially CES2, which is primarily found in the intestine, by everolimus might play a role in drug-drug interactions with coadministered drugs. CES1 and CES2 hydrolyze many drugs and prodrugs (30). Upon oral everolimus administration, local concentrations of everolimus might be high especially in the intestine, and possibly surpass the K i of approximately 20 mmol/L toward CES2.…”

“…This organophosphate irreversibly inhibits carboxylesterases through the generation of a stable phosphate ester covalently attached to the catalytic serine residue in the enzyme active site (30). If everolimus normally binds to the substrate binding site of carboxylesterase, one would expect it to bind no longer if the carboxylesterase has bound BNPP.…”