Biomedical Chemistry: Research and Methods, 2018, 1(3), e00026
The 40th Anniversary of the Institute of Physiologically Active Compounds of the Russian Academy of Sciences

Selective Carboxylesterase Inhibitors for Improving Efficacy, Safety and
Rational use of Ester-Containing Drugs

N.P. Boltneva1*, G.F. Makhaeva1, E.V. Shchegol’kov2, Ya.V. Burgart2, V.I. Saloutin2

1Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severny proezd, Moscow region, Chernogolovka, 142432 Russia,*e-mail: boltneva@ipac.ac.ru
2Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, 22/20, S. Kovalevskoy/Akademicheskaya str., Yekaterinburg, 620990 Russia

Key words: carboxylesterases; prodrugs; ester-containing drugs; inhibitors; polyfluoroalkyl-2-imino-1,3-dione scaffold

DOI: 10.18097/BMCRM00026

The whole version of this paper is available in Russian.

In clinical practice, a large number of prodrugs and active drugs containing an ester, carbamate or amide moiety are used. Carboxylesterase (CaE, EC 3.1.1.1) is the key enzyme of hydrolytic metabolism of such drugs in the body, it largely determines their pharmacokinetics, bioavailability, efficacy and possible toxic effects. Using CaE selective inhibitors as components of combined drug therapy it is possible us to regulate the rate of hydrolytic transformation of ester-containing drugs and opens the possibility of their rational use. The development of effective and selective CaE inhibitors suitable for in vivo application is a new promising approach in medicinal chemistry and pharmacology that allows to improve the efficacy, bioavailability and reduce the side effects of ester-containing drugs.

Figure 1. Structures of some drugs that are substrates of CaE.

Figure 2. Mechanism of CaE-hydrolysis of substrates.

Figure 3. Role of CaE and its inhibitors in the mechanism of action of esterified pro-drugs.

Figure 4. Role of CaE and its inhibitors in the mechanism of action of ester-containing drugs.

Figure 5. Covalent selective inhibitors of carboxylesterase.

Figure 6. Known selective carboxylesterase inhibitors.

Figure 7. New promising CaE inhibitors having 2-imino-3-polyfluoroalkyl-1,3-dione scaffold.

CLOSE
Table 1. Inhibitor activity (IC50, nM) and selectivity of Foxins (alkyl-2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates) I against CaE, AChE and BChE.

CLOSE
Table 2. Esterase profile of some 7-hydroxy-7-polyfluoroalkyl-4,7-dihydroazolo [5,1-c] [1,2,4] triazines II.

ACKNOWLEDGEMENTS

This work was performed within the framework of the RFBR #16-03-00417; biological research - in the framework of the Russian State assignment № 0090-2017-0019, chemical part - in the framework of the Russian State assignment АААА-А18-118020290121-9.

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