Identification and structure-activity relationships of a novel series of estrogen receptor ligands based on 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide.

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Wang P, Min J, Nwachukwu JC, Cavett V, Carlson KE, Guo P, Zhu M, Zheng Y, Dong C, Katzenellenbogen JA, Nettles KW, Zhou HB

Identification and structure-activity relationships of a novel series of estrogen receptor ligands based on 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide.

J Med Chem. 2012 Mar 8;55(5):2324-41. doi: 10.1021/jm201556r. Epub 2012 Feb 21.

PubMed ID
22283328 [ View in PubMed
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Abstract

To develop estrogen receptor (ER) ligands having novel structures and activities, we have explored compounds in which the central hydrophobic core has a more three-dimensional topology than typically found in estrogen ligands and thus exploits the unfilled space in the ligand-binding pocket. Here, we build upon our previous investigations of 7-oxabicyclo[2.2.1]heptene core ligands, by replacing the oxygen bridge with a sulfoxide. These new 7-thiabicyclo[2.2.1]hept-2-ene-7-oxides were conveniently prepared by a Diels-Alder reaction of 3,4-diarylthiophenes with dienophiles in the presence of an oxidant and give cycloadducts with endo stereochemistry. Several new compounds demonstrated high binding affinities with excellent ERalpha selectivity, but unlike oxabicyclic compounds, which are transcriptional antagonists, most thiabicyclic compounds are potent, ERalpha-selective agonists. Modeling suggests that the gain in activity of the thiabicyclic compounds arises from their endo stereochemistry that stabilizes an active ER conformation. Further, the disposition of methyl substituents in the phenyl groups attached to the bicyclic core unit contributes to their binding affinity and subtype selectivity.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
EstradiolEstrogen receptor alphaEC 50 (nM)2.2N/AN/ADetails
EstradiolEstrogen receptor betaEC 50 (nM)11N/AN/ADetails