Synthesis and biological evaluation of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitors based on a thieno[2,3-d]pyrimidin-4(3H)-one core.

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Lilienkampf A, Karkola S, Alho-Richmond S, Koskimies P, Johansson N, Huhtinen K, Vihko K, Wahala K

Synthesis and biological evaluation of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitors based on a thieno[2,3-d]pyrimidin-4(3H)-one core.

J Med Chem. 2009 Nov 12;52(21):6660-71. doi: 10.1021/jm900928k.

PubMed ID

19824648 [ View in PubMed

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Abstract

Many breast tumors are hormone-dependent, and estrogens, especially estradiol (E2), have a pivotal role in their growth and development. 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-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 17beta-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 muM test concentrations, were found to be potent 17beta-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 17beta-HSD1 inhibitors reported to date with 94% inhibition of the recombinant enzyme at 0.1 muM test concentration. Importantly, the majority of these compounds exhibited excellent selectivity over the oxidative isoform 17beta-HSD2 and lacked estrogenic effects in an estrogen receptor (ER) binding assay.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Estrone	Estrogen receptor alpha	EC 50 (nM)	7	N/A	N/A	Details
Estrone	Estrogen receptor beta	EC 50 (nM)	8	N/A	N/A	Details