New drug-like hydroxyphenylnaphthol steroidomimetics as potent and selective 17beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of estrogen-dependent diseases.

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Marchais-Oberwinkler S, Wetzel M, Ziegler E, Kruchten P, Werth R, Henn C, Hartmann RW, Frotscher M

New drug-like hydroxyphenylnaphthol steroidomimetics as potent and selective 17beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of estrogen-dependent diseases.

J Med Chem. 2011 Jan 27;54(2):534-47. doi: 10.1021/jm1009082. Epub 2010 Dec 28.

PubMed ID
21189020 [ View in PubMed
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Abstract

Inhibition of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is a novel and attractive approach to reduce the local levels of the active estrogen 17beta-estradiol in patients with estrogen-dependent diseases like breast cancer or endometriosis. With the aim of optimizing the biological profile of 17beta-HSD1 inhibitors from the hydroxyphenylnaphthol class, structural optimizations were performed at the 1-position of the naphthalene by introduction of different heteroaromatic rings as well as substituted phenyl groups. In the latter class of compounds, which were synthesized applying Suzuki-cross coupling, the 3-methanesulfonamide 15 turned out to be a highly potent 17beta-HSD1 inhibitor (IC(50) = 15 nM in a cell-free assay). It was also very active in the cellular assay (T47D cells, IC(50) = 71 nM) and selective toward 17beta-HSD2 and the estrogen receptors alpha and beta. It showed a good membrane permeation and metabolic stability and was orally available in the rat.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
QuinidineCytochrome P450 2D6IC 50 (nM)10N/AN/ADetails
SulfaphenazoleCytochrome P450 2C9IC 50 (nM)250N/AN/ADetails
TranylcypromineCytochrome P450 2C19IC 50 (nM)3040N/AN/ADetails