Lead Optimization of 17β-HSD1 Inhibitors of the (Hydroxyphenyl)naphthol Sulfonamide Type for the Treatment of Endometriosis

Claudia Henn; Almuth Einspanier; A. Einspanier; Sandrine Marchais-Oberwinkler; Sandrine Marchais‐Oberwinkler; Martin Frotscher; Rolf W Hartmann

doi:10.1021/jm201735j

Lead Optimization of 17β-HSD1 Inhibitors of the (Hydroxyphenyl)naphthol Sulfonamide Type for the Treatment of Endometriosis

Claudia Henn, Almuth Einspanier, A. Einspanier, Sandrine Marchais-Oberwinkler, Sandrine Marchais‐Oberwinkler, Martin Frotscher, Rolf W Hartmann

Journal of medicinal chemistry · 2012 · vol. 55(7) , pp. 3307–3318 · doi:10.1021/jm201735j · PMID:22380653 · W2313213549

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This study optimized (hydroxyphenyl)naphthol sulfonamides, yielding compound 30, a highly active and selective human 17β-HSD1 inhibitor with good intracellular activity, suitable for further ADMET studies and in vivo proof of concept.

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Abstract

The reduction of estrone to estradiol, the most potent estrogen in human, is catalyzed by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). A promising approach for the treatment of estrogen-dependent diseases is the reduction of intracellular estradiol formation by inhibition of 17β-HSD1. For the species-specific optimization of the (hydroxyphenyl)naphthols, a combinatorial approach was applied and enhanced by a focused synthesis that resulted in the aromatic-substituted (hydroxyphenyl)naphthol sulfonamides. Rigidification of 12 led to the 4-indolylsulfonamide 30, which is a highly active and selective human 17β-HSD1 inhibitor, as well as a highly potent and selective inhibitor of 17β-HSD1 from Callithrix jacchus. It shows no affinity to the estrogen receptors α and β and good intracellular activity (T47D). Thus, compound 30 shows good properties for further ADMET studies and might be a candidate for the in vivo proof of concept in C. jacchus.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Estradiol Dehydrogenases Naphthols Sulfonamides Animals Callithrix Cell Line, Tumor Endometriosis Estradiol Dehydrogenases Estrogen Receptor alpha Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptor beta Female Humans Naphthols Naphthols Naphthols Placenta Placenta

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[1] Endometriosis: Role of Ovarian Steroids in Initiation, Maintenance, and Suppression 1980

[2] Peritoneal endometriosis: validation of an in-vivo model 2001

[3] Induction of endometriosis in the marmoset monkey (Callithrix jacchus) 2006

[4] Novel Hydroxysteroid (17β) Dehydrogenase 1 Inhibitors Reverse Estrogen-Induced Endometrial Hyperplasia in Transgenic Mice 2010