Reductive 17beta-hydroxysteroid dehydrogenases in the sulfatase pathway: critical in the cell proliferation of breast cancer.

https://hal.archives-ouvertes.fr/hal-00532101/document

Estrone C15 derivatives—A new class of 17β-hydroxysteroid dehydrogenase type 1 inhibitors

Many breast tumors are hormone-dependent, and estrogens, especially estradiol (E2), have a pivotal role in their growth and development. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a key enzyme in the biosynthesis of female sex steroids, catalyzing the NADPH-dependent reduction of estrone into biologically active estradiol. In this study, a library of fused (di)cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-one based compounds was synthesized, and the biological activities against 17β-HSD1 in a cell-free and in a cell-based assay were evaluated. Several thieno[2,3-d]pyrimidin-4(3H)-one based compounds, at 0.1 and 1 μM test concentrations, were found to be potent 17β-HSD1 inhibitors. For example, 4-(3-hydroxyphenylthio)-1,2,7,8,9,10,11,13-octahydro-13-oxo-[1]benzothieno[2′,3′:4,5]-pyrimido[1,2-a]azepine-3-carboxaldehyde (7f) is one of the most potent nonsteroidal 17β-HSD1 inhibitors reported to date with 94% inhibition of the recombinant enzyme at 0.1 μM test concentration. Importantly, the majority of...

Synthesis and Biological Evaluation of 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1) Inhibitors Based on a Thieno[2,3-d]pyrimidin-4(3H)-one Core

The invention relates to 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1) inhibitors, the production thereof, and the use thereof for treating and preventing hormone-dependent, especially estrogen-dependent or androgen-dependent diseases.

17beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of hormone-dependent diseases

Steroid-related cancers can be treated by inhibitors of steroid metabolism. In searching for new inhibitors of human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD 1) for the treatment of breast cancer or endometriosis, novel substances based on 15-substituted estrone were validated. We checked the specificity for different 17beta-HSD types and species. Compounds were tested for specificity in vitro not only towards recombinant human 17beta-HSD types 1, 2, 4, 5 and 7 but also against 17beta-HSD 1 of several other species including marmoset, pig, mouse, and rat. The latter are used in the processes of pharmacophore screening. We present the quantification of inhibitor preferences between human and animal models. Profound differences in the susceptibility to inhibition of steroid conversion among all 17beta-HSDs analyzed were observed. Especially, the rodent 17beta-HSDs 1 were significantly less sensitive to inhibition compared to the human ortholog, while the most similar inhibition pattern to the human 17beta-HSD 1 was obtained with the marmoset enzyme. Molecular docking experiments predicted estrone as the most potent inhibitor. The best performing compound in enzymatic assays was also highly ranked by docking scoring for the human enzyme. However, species-specific prediction of inhibitor performance by molecular docking was not possible. We show that experiments with good candidate compounds would out-select them in the rodent model during preclinical optimization steps. Potentially active human-relevant drugs, therefore, would no longer be further developed. Activity and efficacy screens in heterologous species systems must be evaluated with caution.

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Species used for drug testing reveal different inhibition susceptibility for 17beta-hydroxysteroid dehydrogenase type 1.

The present invention relates to novel 3, 15 substituted estrone derivatives which represent inhibitory compounds of the 17β-hydroxysteroid dehydrogenase type I (17β-HSD1), to their salts, to pharmaceutical preparations containing these compounds and to processes for the preparation of these compounds. Furthermore, the invention concerns the therapeutic use of said novel 3, 15 substituted estrone derivatives, particularly their use in the treatment or prevention of steroid hor­mone dependent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of 17β-hydroxysteroid dehydrogenase type I enzymes and/or requiring the lowering of the endogenous 17β-estradiol concentration. In addition, the present invention relates to the general use of selective 17β-hydroxysteroid dehydrogenase type 1 inhibitors which possess in addition no or only pure antagonistic binding affinities to the estrogen receptor for the treatment and prevention of benign gynaecological disorders, in particular endometriosis.

NOVEL 17beta HYDROXYSTEROID DEHYDROGENASE TYPE I INHIBITORS

3,15-substituted estrone compounds which act as inhibitors of 17β-hydroxysteroid dehydrogenase type I (17β-HSD1), salts thereof, pharmaceutical preparations containing such compounds, processes for preparing such compounds, and therapeutic uses of such compounds, particularly in the treatment or inhibition of steroid hormone dependent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of 17β-hydroxysteroid dehydrogenase type I enzymes and/or requiring the lowering of the endogenous 17β-estradiol concentration, as well as the general use of selective 17β-hydroxysteroid dehydrogenase type 1 inhibitors which possess in addition no or only pure antagonistic binding affinities to the estrogen receptor for the treatment or inhibition of benign gynecological disorders, particularly endometriosis.

Johannes Bernardus Everardus Hulshof

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NOVEL 17beta HYDROXYSTEROID DEHYDROGENASE TYPE I INHIBITORS

17β-hydroxysteroid dehydrogenase type I inhibitors