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New insights into the SAR and binding modes of bis(hydroxyphenyl)thiophenes and -benzenes: influence of additional substituents on 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitory activity and selectivity.

17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is responsible for the catalytic reduction of weakly active E1 to highly potent E2. E2 stimulates the proliferation of hormone-dependent diseases via activation of the estrogen receptor alpha (ERalpha). Because of the overexpression of 17beta-... Full description

Journal Title: Journal of medicinal chemistry November 12, 2009, Vol.52(21), pp.6724-6743
Main Author: Bey, Emmanuel
Other Authors: Marchais-Oberwinkler, Sandrine , Negri, Matthias , Kruchten, Patricia , Oster, Alexander , Klein, Tobias , Spadaro, Alessandro , Werth, Ruth , Frotscher, Martin , Birk, Barbara , Hartmann, Rolf W
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1520-4804 ; DOI: 10.1021/jm901195w
Link: http://search.proquest.com/docview/734127997/?pq-origsite=primo
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title: New insights into the SAR and binding modes of bis(hydroxyphenyl)thiophenes and -benzenes: influence of additional substituents on 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitory activity and selectivity.
format: Article
creator:
  • Bey, Emmanuel
  • Marchais-Oberwinkler, Sandrine
  • Negri, Matthias
  • Kruchten, Patricia
  • Oster, Alexander
  • Klein, Tobias
  • Spadaro, Alessandro
  • Werth, Ruth
  • Frotscher, Martin
  • Birk, Barbara
  • Hartmann, Rolf W
subjects:
  • 17-Hydroxysteroid Dehydrogenases–Antagonists & Inhibitors
  • Administration, Oral–Chemistry
  • Animals–Chemical Synthesis
  • Benzene Derivatives–Chemistry
  • Biphenyl Compounds–Pharmacology
  • Crystallography, X-Ray–Chemical Synthesis
  • Cytochrome P-450 Enzyme Inhibitors–Chemistry
  • Estradiol Dehydrogenases–Pharmacology
  • Estrogen Receptor Alpha–Antagonists & Inhibitors
  • Estrogen Receptor Beta–Chemistry
  • Female–Chemistry
  • Humans–Antagonists & Inhibitors
  • Isoenzymes–Enzymology
  • Liver–Chemical Synthesis
  • Male–Chemistry
  • Models, Molecular–Pharmacology
  • Phenols
ispartof: Journal of medicinal chemistry, November 12, 2009, Vol.52(21), pp.6724-6743
description: 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is responsible for the catalytic reduction of weakly active E1 to highly potent E2. E2 stimulates the proliferation of hormone-dependent diseases via activation of the estrogen receptor alpha (ERalpha). Because of the overexpression of 17beta-HSD1 in mammary tumors, this enzyme should be an attractive target for the treatment of estrogen-dependent pathologies. Recently, we have reported on a series of potent 17beta-HSD1 inhibitors: bis(hydroxyphenyl) azoles, thiophenes, and benzenes. In this paper, different substituents are introduced into the core structure and the biological properties of the corresponding inhibitors are evaluated. Computational methods and analysis of different X-rays of 17beta-HSD1 lead to identification of two different binding modes for these inhibitors. The fluorine compound 23 exhibits an IC(50) of 8 nM and is the most potent nonsteroidal inhibitor described so far. It also shows a high selectivity (17beta-HSD2,...
language: eng
source:
identifier: E-ISSN: 1520-4804 ; DOI: 10.1021/jm901195w
fulltext: fulltext
issn:
  • 15204804
  • 1520-4804
url: Link


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titleNew insights into the SAR and binding modes of bis(hydroxyphenyl)thiophenes and -benzenes: influence of additional substituents on 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitory activity and selectivity.
creatorBey, Emmanuel ; Marchais-Oberwinkler, Sandrine ; Negri, Matthias ; Kruchten, Patricia ; Oster, Alexander ; Klein, Tobias ; Spadaro, Alessandro ; Werth, Ruth ; Frotscher, Martin ; Birk, Barbara ; Hartmann, Rolf W
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ispartofJournal of medicinal chemistry, November 12, 2009, Vol.52(21), pp.6724-6743
identifierE-ISSN: 1520-4804 ; DOI: 10.1021/jm901195w
subject17-Hydroxysteroid Dehydrogenases–Antagonists & Inhibitors ; Administration, Oral–Chemistry ; Animals–Chemical Synthesis ; Benzene Derivatives–Chemistry ; Biphenyl Compounds–Pharmacology ; Crystallography, X-Ray–Chemical Synthesis ; Cytochrome P-450 Enzyme Inhibitors–Chemistry ; Estradiol Dehydrogenases–Pharmacology ; Estrogen Receptor Alpha–Antagonists & Inhibitors ; Estrogen Receptor Beta–Chemistry ; Female–Chemistry ; Humans–Antagonists & Inhibitors ; Isoenzymes–Enzymology ; Liver–Chemical Synthesis ; Male–Chemistry ; Models, Molecular–Pharmacology ; Phenols
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description17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is responsible for the catalytic reduction of weakly active E1 to highly potent E2. E2 stimulates the proliferation of hormone-dependent diseases via activation of the estrogen receptor alpha (ERalpha). Because of the overexpression of 17beta-HSD1 in mammary tumors, this enzyme should be an attractive target for the treatment of estrogen-dependent pathologies. Recently, we have reported on a series of potent 17beta-HSD1 inhibitors: bis(hydroxyphenyl) azoles, thiophenes, and benzenes. In this paper, different substituents are introduced into the core structure and the biological properties of the corresponding inhibitors are evaluated. Computational methods and analysis of different X-rays of 17beta-HSD1 lead to identification of two different binding modes for these inhibitors. The fluorine compound 23 exhibits an IC(50) of 8 nM and is the most potent nonsteroidal inhibitor described so far. It also shows a high selectivity (17beta-HSD2,...
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titleNew insights into the SAR and binding modes of bis(hydroxyphenyl)thiophenes and -benzenes: influence of additional substituents on 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitory activity and selectivity.
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017-Hydroxysteroid Dehydrogenases–Antagonists & Inhibitors
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2Animals–Chemical Synthesis
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titleNew insights into the SAR and binding modes of bis(hydroxyphenyl)thiophenes and -benzenes: influence of additional substituents on 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitory activity and selectivity.
authorBey, Emmanuel ; Marchais-Oberwinkler, Sandrine ; Negri, Matthias ; Kruchten, Patricia ; Oster, Alexander ; Klein, Tobias ; Spadaro, Alessandro ; Werth, Ruth ; Frotscher, Martin ; Birk, Barbara ; Hartmann, Rolf W
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2Animals–Chemical Synthesis
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4Biphenyl Compounds–Pharmacology
5Crystallography, X-Ray–Chemical Synthesis
6Cytochrome P-450 Enzyme Inhibitors–Chemistry
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8Estrogen Receptor Alpha–Antagonists & Inhibitors
9Estrogen Receptor Beta–Chemistry
10Female–Chemistry
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14Male–Chemistry
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