Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole

Katharina R Beck; Murielle Bächler; Anna Vuorinen; Sandra Wagner; Muhammad Akram; Ulrich Griesser; Veronika Temml; Petra Klusonova; Hideaki Yamaguchi; Daniela Schuster; Alex Odermatt

doi:10.1016/j.bcp.2017.01.010

Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole

Biochem Pharmacol. 2017 Apr 15:130:93-103. doi: 10.1016/j.bcp.2017.01.010. Epub 2017 Jan 25.

Authors

Affiliations

¹ Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: katharina.beck@unibas.ch.
² Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: murielle.baechler@stud.unibas.ch.
³ Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: anna.vuorinen1@gmail.com.
⁴ Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), Computer Aided Molecular Design Group, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: sandra.wagner@student.uibk.ac.at.
⁵ Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), Computer Aided Molecular Design Group, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: muhammad.akram@uibk.ac.at.
⁶ Institute of Pharmacy/Pharmaceutical Technology, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: ulrich.griesser@uibk.ac.at.
⁷ Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), Computer Aided Molecular Design Group, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: veronika.temml@uibk.ac.at.
⁸ Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: petra.klusonova@unibas.ch.
⁹ Department of Applied Biological Chemistry, Meijo University, Nagoya 468-8502, Japan. Electronic address: hyamagu@meijo-u.ac.jp.
¹⁰ Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), Computer Aided Molecular Design Group, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: daniela.schuster@uibk.ac.at.
¹¹ Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: alex.odermatt@unibas.ch.

Abstract

Impaired 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)-dependent cortisol inactivation can lead to electrolyte dysbalance, hypertension and cardiometabolic disease. Furthermore, placental 11β-HSD2 essentially protects the fetus from high maternal glucocorticoid levels, and its impaired function has been associated with altered fetal growth and a higher risk for cardio-metabolic diseases in later life. Despite its important role, 11β-HSD2 is not included in current off-target screening approaches. To identify potential 11β-HSD inhibitors among approved drugs, a pharmacophore model was used for virtual screening, followed by biological assessment of selected hits. This led to the identification of several azole fungicides as 11β-HSD inhibitors, showing a significant structure-activity relationship between azole scaffold size, 11β-HSD enzyme selectivity and inhibitory potency. A hydrophobic linker connecting the azole ring to the other, more polar end of the molecule was observed to be favorable for 11β-HSD2 inhibition and selectivity over 11β-HSD1. The most potent 11β-HSD2 inhibition, using cell lysates expressing recombinant human 11β-HSD2, was obtained for itraconazole (IC₅₀ 139±14nM), its active metabolite hydroxyitraconazole (IC₅₀ 223±31nM) and posaconazole (IC₅₀ 460±98nM). Interestingly, experiments with mouse and rat kidney homogenates showed considerably lower inhibitory activity of these compounds towards 11β-HSD2, indicating important species-specific differences. Thus, 11β-HSD2 inhibition by these compounds is likely to be overlooked in preclinical rodent studies. Inhibition of placental 11β-HSD2 by these compounds, in addition to the known inhibition of cytochrome P450 enzymes and P-glycoprotein efflux transport, might contribute to elevated local cortisol levels, thereby affecting fetal programming.

Keywords: 11β-Hydroxysteroid dehydrogenase; Albendazole (PubChem CID: 2082); Butoconazole (PubChem CID: 47472); Climbazole (PubChem CID: 37907); Glucocorticoid; Hydroxyitraconazole (PubChem CID: 108222); Itraconazole; Itraconazole (PubChem CID: 55283); Ketoconazole (PubChem CID: 47576); Posaconazole; Posaconazole (PubChem CID: 468595); Reproductive toxicity; Sertaconazole (PubChem CID: 65863); Terconazole (PubChem CID: 441383); Tioconazole (PubChem CID: 5482); Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 2 / antagonists & inhibitors*
Animals
Antifungal Agents / chemistry
Antifungal Agents / pharmacology*
Enzyme Inhibitors / pharmacology*
HEK293 Cells
Humans
Itraconazole / chemistry
Itraconazole / pharmacology*
Rats
Structure-Activity Relationship
Triazoles / chemistry
Triazoles / pharmacology*

Substances

Antifungal Agents
Enzyme Inhibitors
Triazoles
Itraconazole
posaconazole
11-beta-Hydroxysteroid Dehydrogenase Type 2

Grants and funding

P 26782/FWF_/Austrian Science Fund FWF/Austria