Phenylbenzenesulfonates and -sulfonamides as 17β-hydroxysteroid dehydrogenase type 2 inhibitors: Synthesis and SAR-analysis

Anna Vuorinen; Roger T Engeli; Susanne Leugger; Christoph R Kreutz; Daniela Schuster; Alex Odermatt; Barbara Matuszczak

doi:10.1016/j.bmcl.2017.05.005

Phenylbenzenesulfonates and -sulfonamides as 17β-hydroxysteroid dehydrogenase type 2 inhibitors: Synthesis and SAR-analysis

Bioorg Med Chem Lett. 2017 Jul 1;27(13):2982-2985. doi: 10.1016/j.bmcl.2017.05.005. Epub 2017 May 4.

Authors

Anna Vuorinen¹, Roger T Engeli², Susanne Leugger², Christoph R Kreutz³, Daniela Schuster⁴, Alex Odermatt⁵, Barbara Matuszczak⁶

Affiliations

¹ Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria; Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
² Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
³ Institute of Organic Chemistry and Center for Molecular Biosciences (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
⁴ Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
⁵ Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: Alex.Odermatt@unibas.ch.
⁶ Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: Barbara.Matuszczak@uibk.ac.at.

PMID: 28506753
DOI: 10.1016/j.bmcl.2017.05.005

Abstract

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the potent estrogen estradiol into the weakly active keto form estrone. Because of its expression in bone, inhibition of 17β-HSD2 provides an attractive strategy for the treatment of osteoporosis, a condition that is often caused by a decrease of the active sex steroids. Currently, there are no drugs on the market targeting 17β-HSD2, but in multiple studies, synthesis and biological evaluation of promising 17β-HSD2 inhibitors have been reported. Our previous work led to the identification of phenylbenzenesulfonamides and -sulfonates as new 17β-HSD2 inhibitors by ligand-based pharmacophore modeling and virtual screening. In this study, new molecules representing this scaffold were synthesized and tested in vitro for their 17β-HSD2 activity to derive more profound structure-activity relationship rules.

Keywords: 17β-HSD2; Estrogen; Inhibitor; Osteoporosis; Virtual screening.

Publication types

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

MeSH terms

Benzenesulfonates / chemical synthesis
Benzenesulfonates / chemistry
Benzenesulfonates / pharmacology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Estradiol Dehydrogenases / antagonists & inhibitors*
Estradiol Dehydrogenases / metabolism
Humans
Molecular Structure
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Benzenesulfonates
Enzyme Inhibitors
Sulfonamides
phenylbenzenesulfonate
Estradiol Dehydrogenases
HSD17B2 protein, human