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

Emmanuel Bey; Sandrine Marchais-Oberwinkler; Matthias Negri; Patricia Kruchten; Alexander Oster; Tobias Klein; Alessandro Spadaro; Ruth Werth; Martin Frotscher; Barbara Birk; Rolf W Hartmann

doi:10.1021/jm901195w

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

J Med Chem. 2009 Nov 12;52(21):6724-43. doi: 10.1021/jm901195w.

Authors

Emmanuel Bey¹, Sandrine Marchais-Oberwinkler, Matthias Negri, Patricia Kruchten, Alexander Oster, Tobias Klein, Alessandro Spadaro, Ruth Werth, Martin Frotscher, Barbara Birk, Rolf W Hartmann

Affiliation

¹ Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 15 11 50, D-66041 Saarbrucken, Germany.

PMID: 19831396
DOI: 10.1021/jm901195w

Abstract

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, ERalpha) and excellent pharmacokinetic properties after peroral application to rats.

Publication types

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

MeSH terms

17-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
17-Hydroxysteroid Dehydrogenases / chemistry
Administration, Oral
Animals
Benzene Derivatives / chemical synthesis*
Benzene Derivatives / chemistry
Benzene Derivatives / pharmacology
Biphenyl Compounds / chemical synthesis
Biphenyl Compounds / chemistry
Biphenyl Compounds / pharmacology
Crystallography, X-Ray
Cytochrome P-450 Enzyme Inhibitors
Estradiol Dehydrogenases / antagonists & inhibitors
Estrogen Receptor alpha / chemistry
Estrogen Receptor beta / chemistry
Female
Humans
Isoenzymes / antagonists & inhibitors
Liver / enzymology
Male
Models, Molecular
Phenols / chemical synthesis*
Phenols / chemistry
Phenols / pharmacology
Placenta / enzymology
Pregnancy
Protein Binding
Rats
Rats, Wistar
Stereoisomerism
Structure-Activity Relationship
Terphenyl Compounds / chemical synthesis
Terphenyl Compounds / chemistry
Terphenyl Compounds / pharmacology
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacology
Thiophenes / chemical synthesis*
Thiophenes / chemistry
Thiophenes / pharmacology

Substances

2-fluoro-4-(5-(3-hydroxyphenyl)-2-thienyl)phenol
Benzene Derivatives
Biphenyl Compounds
Cytochrome P-450 Enzyme Inhibitors
Estrogen Receptor alpha
Estrogen Receptor beta
Isoenzymes
Phenols
Terphenyl Compounds
Thiazoles
Thiophenes
17-Hydroxysteroid Dehydrogenases
3 (or 17)-beta-hydroxysteroid dehydrogenase
Estradiol Dehydrogenases
HSD17B2 protein, human