Synthesis and evaluation of indomethacin prodrugs with a diester structure that are metabolically activated by human carboxylesterases

Abstract

1. Carboxylesterase (CES) has been studied extensively, mostly with substrates in the monoester structures. We investigated the relationship between indomethacin diester prodrugs and metabolic activation by microsomes and recombinant human CES.

2. Eight indomethacin diester prodrugs were synthesised in two steps. They were used as substrates and hydrolysis rates were calculated.

3. As a result, the major hydrolysis enzyme was CES. The hydrolysis rate of recombinant CES2A1 was comparable to that of recombinant CES1A1.

4. In this study, by changing the structure of the prodrug to a diester structure, it was found that CES2 activity was equivalent to CES1 activity.

5. It should be noted that the use of diester prodrugs in prodrug discovery, where organ-specific hydrolysis reactions are expected, may not yield the expected results.

Keywords:

• Carboxylesterase
• Prodrug
• Metabolic activation
• Diester structure
• Indomethacin

Acknowledgments

The authors thank the HAB Research Organization for providing human livers.

Disclosure statement

The authors declare that there is no conflict of interest.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.