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Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β‐Hydroxysteroid Dehydrogenase Type 1 (17 β‐HSD1): The Role of the Bicyclic Moiety

An attractive target that has still to be explored for the treatment of estrogen‐dependent diseases, such as breast cancer and endometriosis, is the enzyme responsible for the last step in the biosynthesis of estradiol (E2): 17β‐hydroxysteroid dehydrogenase type 1 (17β‐HSD1). It catalyzes the reduct... Full description

Journal Title: ChemMedChem 07 March 2011, Vol.6(3), pp.476-487
Main Author: Oster, Alexander
Other Authors: Klein, Tobias , Henn, Claudia , Werth, Ruth , Marchais‐Oberwinkler, Sandrine , Frotscher, Martin , Hartmann, Rolf W.
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 1860-7179 ; E-ISSN: 1860-7187 ; DOI: 10.1002/cmdc.201000457
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title: Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β‐Hydroxysteroid Dehydrogenase Type 1 (17 β‐HSD1): The Role of the Bicyclic Moiety
format: Article
creator:
  • Oster, Alexander
  • Klein, Tobias
  • Henn, Claudia
  • Werth, Ruth
  • Marchais‐Oberwinkler, Sandrine
  • Frotscher, Martin
  • Hartmann, Rolf W.
subjects:
  • 17β‐Hsd1
  • Breast Cancer
  • Endometriosis
  • Inhibitors
  • Structure–Activity Relationships
ispartof: ChemMedChem, 07 March 2011, Vol.6(3), pp.476-487
description: An attractive target that has still to be explored for the treatment of estrogen‐dependent diseases, such as breast cancer and endometriosis, is the enzyme responsible for the last step in the biosynthesis of estradiol (E2): 17β‐hydroxysteroid dehydrogenase type 1 (17β‐HSD1). It catalyzes the reduction of the weakly active estrone (E1) into E2, which is the most potent estrogen in humans. Inhibition of 17β‐HSD1 lowers intracellular E2 concentrations and thus presents a therapeutic target for estrogen‐dependent pathologies. Recently, we reported a new class of highly active and selective 17β‐HSD1 inhibitors: bicyclic substituted hydroxyphenylmethanones. Here, further structural variations on the bicyclic moiety are described, especially focusing on the exchange of its hydroxy function. Twenty‐nine novel inhibitors were synthesized and evaluated for 17β‐HSD1 inhibition in a cell‐free and cellular assay, for selectivity toward 17βHSD2 and estrogen receptors (ER) alpha and beta, as well as for metabolic stability. The best compound exhibited IC values of 12 n (cell‐free assay) and 78 n (cellular assay), high selectivity for 17β‐HSD1, and reasonable metabolic stability. A molecular docking study provided insight into the protein–ligand interactions of this compound with 17β‐HSD1. is a promising strategy for the treatment of estrogen‐dependent diseases like breast cancer and endometriosis. Modifications on the bicyclic moiety in bicyclic substituted hydroxyphenylmethanones led to sulphonamide derivatives with high inhibitory activity (IC=12 n), remarkable selectivity, and good metabolic stability.
language: eng
source:
identifier: ISSN: 1860-7179 ; E-ISSN: 1860-7187 ; DOI: 10.1002/cmdc.201000457
fulltext: fulltext
issn:
  • 1860-7179
  • 18607179
  • 1860-7187
  • 18607187
url: Link


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titleBicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β‐Hydroxysteroid Dehydrogenase Type 1 (17 β‐HSD1): The Role of the Bicyclic Moiety
creatorOster, Alexander ; Klein, Tobias ; Henn, Claudia ; Werth, Ruth ; Marchais‐Oberwinkler, Sandrine ; Frotscher, Martin ; Hartmann, Rolf W.
ispartofChemMedChem, 07 March 2011, Vol.6(3), pp.476-487
identifier
subject17β‐Hsd1 ; Breast Cancer ; Endometriosis ; Inhibitors ; Structure–Activity Relationships
descriptionAn attractive target that has still to be explored for the treatment of estrogen‐dependent diseases, such as breast cancer and endometriosis, is the enzyme responsible for the last step in the biosynthesis of estradiol (E2): 17β‐hydroxysteroid dehydrogenase type 1 (17β‐HSD1). It catalyzes the reduction of the weakly active estrone (E1) into E2, which is the most potent estrogen in humans. Inhibition of 17β‐HSD1 lowers intracellular E2 concentrations and thus presents a therapeutic target for estrogen‐dependent pathologies. Recently, we reported a new class of highly active and selective 17β‐HSD1 inhibitors: bicyclic substituted hydroxyphenylmethanones. Here, further structural variations on the bicyclic moiety are described, especially focusing on the exchange of its hydroxy function. Twenty‐nine novel inhibitors were synthesized and evaluated for 17β‐HSD1 inhibition in a cell‐free and cellular assay, for selectivity toward 17βHSD2 and estrogen receptors (ER) alpha and beta, as well as for metabolic stability. The best compound exhibited IC values of 12 n (cell‐free assay) and 78 n (cellular assay), high selectivity for 17β‐HSD1, and reasonable metabolic stability. A molecular docking study provided insight into the protein–ligand interactions of this compound with 17β‐HSD1. is a promising strategy for the treatment of estrogen‐dependent diseases like breast cancer and endometriosis. Modifications on the bicyclic moiety in bicyclic substituted hydroxyphenylmethanones led to sulphonamide derivatives with high inhibitory activity (IC=12 n), remarkable selectivity, and good metabolic stability.
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titleBicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β‐Hydroxysteroid Dehydrogenase Type 1 (17 β‐HSD1): The Role of the Bicyclic Moiety
descriptionAn attractive target that has still to be explored for the treatment of estrogen‐dependent diseases, such as breast cancer and endometriosis, is the enzyme responsible for the last step in the biosynthesis of estradiol (E2): 17β‐hydroxysteroid dehydrogenase type 1 (17β‐HSD1). It catalyzes the reduction of the weakly active estrone (E1) into E2, which is the most potent estrogen in humans. Inhibition of 17β‐HSD1 lowers intracellular E2 concentrations and thus presents a therapeutic target for estrogen‐dependent pathologies. Recently, we reported a new class of highly active and selective 17β‐HSD1 inhibitors: bicyclic substituted hydroxyphenylmethanones. Here, further structural variations on the bicyclic moiety are described, especially focusing on the exchange of its hydroxy function. Twenty‐nine novel inhibitors were synthesized and evaluated for 17β‐HSD1 inhibition in a cell‐free and cellular assay, for selectivity toward 17βHSD2 and estrogen receptors (ER) alpha and beta, as well as for metabolic stability. The best compound exhibited IC values of 12 n (cell‐free assay) and 78 n (cellular assay), high selectivity for 17β‐HSD1, and reasonable metabolic stability. A molecular docking study provided insight into the protein–ligand interactions of this compound with 17β‐HSD1. is a promising strategy for the treatment of estrogen‐dependent diseases like breast cancer and endometriosis. Modifications on the bicyclic moiety in bicyclic substituted hydroxyphenylmethanones led to sulphonamide derivatives with high inhibitory activity (IC=12 n), remarkable selectivity, and good metabolic stability.
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abstractAn attractive target that has still to be explored for the treatment of estrogen‐dependent diseases, such as breast cancer and endometriosis, is the enzyme responsible for the last step in the biosynthesis of estradiol (E2): 17β‐hydroxysteroid dehydrogenase type 1 (17β‐HSD1). It catalyzes the reduction of the weakly active estrone (E1) into E2, which is the most potent estrogen in humans. Inhibition of 17β‐HSD1 lowers intracellular E2 concentrations and thus presents a therapeutic target for estrogen‐dependent pathologies. Recently, we reported a new class of highly active and selective 17β‐HSD1 inhibitors: bicyclic substituted hydroxyphenylmethanones. Here, further structural variations on the bicyclic moiety are described, especially focusing on the exchange of its hydroxy function. Twenty‐nine novel inhibitors were synthesized and evaluated for 17β‐HSD1 inhibition in a cell‐free and cellular assay, for selectivity toward 17βHSD2 and estrogen receptors (ER) alpha and beta, as well as for metabolic stability. The best compound exhibited IC values of 12 n (cell‐free assay) and 78 n (cellular assay), high selectivity for 17β‐HSD1, and reasonable metabolic stability. A molecular docking study provided insight into the protein–ligand interactions of this compound with 17β‐HSD1. is a promising strategy for the treatment of estrogen‐dependent diseases like breast cancer and endometriosis. Modifications on the bicyclic moiety in bicyclic substituted hydroxyphenylmethanones led to sulphonamide derivatives with high inhibitory activity (IC=12 n), remarkable selectivity, and good metabolic stability.
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pubWILEY‐VCH Verlag
doi10.1002/cmdc.201000457
pages476-487
date2011-03-07