Design, synthesis, biological evaluation and pharmacokinetics of bis(hydroxyphenyl) substituted azoles, thiophenes, benzenes, and aza-benzenes as potent and selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1)

Emmanuel Bey, Sandrine Marchais-Oberwinkler, Ruth Werth, Matthias Negri, Yaseen A Al-Soud, Patricia Kruchten, Alexander Oster, Martin Frotscher, Barbara Birk, Rolf W Hartmann
Journal of medicinal chemistry · 2008 · doi:10.1021/jm8006917 · PMID:18855374
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This study synthesized and evaluated 39 bis(hydroxyphenyl) azoles, thiophenes, benzenes, and aza-benzenes, identifying potent and selective nonsteroidal inhibitors of 17beta-HSD1 with promising pharmacokinetic properties.

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The paper reports the design, synthesis, biological evaluation, and pharmacokinetics of bis(hydroxyphenyl) substituted azoles, thiophenes, benzenes, and aza-benzenes as nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). Using a tritiated substrate assay, the compounds’ inhibitory potency was measured by incubating tritiated E1 with 17β-HSD1 (and cofactor) and quantifying labeled E2 formation by HPLC, yielding a range of IC50 values (e.g., 50 nM to millimolar). The provided data also include assays against 17β-HSD2 using tritiated E2, showing comparatively weaker inhibition across many entries (generally higher IC50). The paper’s excerpted content does not specify the pharmacokinetic results or explicitly stated limitations, which is a major caveat for interpreting selectivity and in vivo relevance. This paper is relevant to endometriosis through its focus on 17β-HSD1 inhibition, a pathway tied to estrogen metabolism that has been implicated in endometriosis lesion biology.

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Abstract

17beta-Estradiol (E2), the most potent female sex hormone, stimulates the growth of mammary tumors and endometriosis via activation of the estrogen receptor alpha (ERalpha). 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1), which is responsible for the catalytic reduction of the weakly active estrogen estrone (E1) into E2, is therefore discussed as a novel drug target. Recently, we have discovered a 2,5-bis(hydroxyphenyl) oxazole to be a potent inhibitor of 17beta-HSD1. In this paper, further structural optimizations were performed: 39 bis(hydroxyphenyl) azoles, thiophenes, benzenes, and aza-benzenes were synthesized and their biological properties were evaluated. The most promising compounds of this study show enhanced IC 50 values in the low nanomolar range, a high selectivity toward 17beta-HSD2, a low binding affinity to ERalpha, a good metabolic stability in rat liver microsomes, and a reasonable pharmacokinetic profile after peroral application. Calculation of the molecular electrostatic potentials revealed a correlation between 17beta-HSD1 inhibition and the electron density distribution.
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Report error Found 55 Enz. Inhib. hit(s) with all data for entry = 2887 Affinity DataIC50: 50nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 69nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 77nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 101nMAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 151nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 169nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 173nMAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 173nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 185nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 201nMAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 243nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 336nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 342nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 413nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 455nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 471nMAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 559nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 602nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 745nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+3nMAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+3nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+3nMAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+3nMAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+3nMAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+3nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 1.27E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 1.69E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 1.95E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 2.19E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 2.22E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 2.26E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 2.34E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 2.50E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 3.40E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 4.00E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 4.51E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 5.00E+3nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 5.00E+3nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 5.00E+3nMpH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 5.10E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataIC50: 5.50E+3nMAssay Description:Tritiated E2 was incubated with 17beta-HSD2, cofactor, and inhibitor. The amount of labeled E1 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DatapH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DatapH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DatapH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DatapH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DatapH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DatapH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DatapH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DataAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair Affinity DatapH: 7.0 T: 2°CAssay Description:Tritiated E1 was incubated with 17beta-HSD1, cofactor, and inhibitor. The amount of labeled E2 formed was quantified by HPLC. Detection and quantific...More data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

17-Hydroxysteroid Dehydrogenases Drug Design Enzyme Inhibitors Enzyme Inhibitors 17-Hydroxysteroid Dehydrogenases 17-Hydroxysteroid Dehydrogenases Animals Aza Compounds Aza Compounds Aza Compounds Aza Compounds Azoles Azoles Azoles Azoles Benzene Benzene Benzene Benzene Caco-2 Cells

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