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

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 13; pp. 2982 - 2985
• Main Authors: Vuorinen, Anna, Engeli, Roger T., Leugger, Susanne, Kreutz, Christoph R., Schuster, Daniela, Odermatt, Alex, Matuszczak, Barbara
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.07.2017; Elsevier
• Subjects: 17β-HSD2; Benzenesulfonates - chemical synthesis; Benzenesulfonates - chemistry; Benzenesulfonates - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Estradiol Dehydrogenases - antagonists & inhibitors; Estradiol Dehydrogenases - metabolism; Estrogen; Humans; Inhibitor; Life Sciences & Biomedicine; Molecular Structure; Osteoporosis; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Virtual screening; Virtual screening; Osteoporosis; Inhibitor; 17β-HSD2; Estrogen; LOCALIZATION; HEPATOCYTES; MANAGEMENT; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-2; PLACENTA; TOXICITY; DISCOVERY; 17 beta-HSD2; POSTMENOPAUSAL WOMEN; EXPRESSION
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.05.005

[Display omitted] 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.