title: Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker.
abstract: Estradiol is the most potent estrogen in humans. It is known to be involved in the development and proliferation of estrogen dependent diseases such as breast cancer and endometriosis. The last step of its biosynthesis is catalyzed by 17β-hydroxysteroid dehydrogenase type 1 (17β- HSD1) which consequently is a promising target for the treatment of these diseases. Recently, we reported on bicyclic substituted hydroxyphenylmethanones as potent inhibitors of 17β-HSD1. The present study focuses on rational structural modifications in this compound class with the aim of gaining more insight into its structure-activity relationship (SAR). (4-Hydroxyphenyl)-(5-(3-hydroxyphenylsulfanyl)-thiophen-2-yl)methanone (25) was discovered as a member of a novel potent class of human 17β-HSD1 inhibitors. Computational methods were used to elucidate its interactions with the target protein. The compound showed activity also towards the murine 17β-HSD1 enzyme and thus is a starting point for the design of compounds suitable for evaluation in an animal disease model.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Abdelsamie
authors.affiliation: ElexoPharm GmbH, Campus C11, D-66123 Saarbrücken, Germany.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bey
authors.affiliation: ElexoPharm GmbH, Campus C11, D-66123 Saarbrücken, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Hanke
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C23, D-66123 Saarbrücken, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Empting
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C23, D-66123 Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany. Electronic address: m.frotscher@mx.uni-saarland.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D010636:Phenols; D013440:Sulfides; D015067:17-Hydroxysteroid Dehydrogenases
keywords: Bicyclic substituted hydroxyphenylmethanones (BSHs); Estrogen mimetics; Estrogen-dependent diseases; Human 17β-Hydroxysteroid dehydrogenase type 1 (h17β-HSD1) inhibitors; Non-steroidal inhibitors; m17β-HSD1