title: Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole.
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 (IC50139±14nM), its active metabolite hydroxyitraconazole (IC50223±31nM) and posaconazole (IC50460±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.
authors.affiliation: 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.
authors.forename: Katharina R
authors.initials: KR
authors.lastname: Beck
authors.affiliation: 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.
authors.forename: Murielle
authors.initials: M
authors.lastname: Bächler
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Vuorinen
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Wagner
authors.affiliation: 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.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Akram
authors.affiliation: Institute of Pharmacy/Pharmaceutical Technology, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: ulrich.griesser@uibk.ac.at.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Griesser
authors.affiliation: 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.
authors.forename: Veronika
authors.initials: V
authors.lastname: Temml
authors.affiliation: 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.
authors.forename: Petra
authors.initials: P
authors.lastname: Klusonova
authors.affiliation: Department of Applied Biological Chemistry, Meijo University, Nagoya 468-8502, Japan. Electronic address: hyamagu@meijo-u.ac.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: 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.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.affiliation: 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.
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors*; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D017964:Itraconazole / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D014230:Triazoles; D017964:Itraconazole; C101425:posaconazole; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2
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