Benzothiophene selective estrogen receptor modulators with modulated oxidative activity and receptor affinity.

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Qin Z, Kastrati I, Chandrasena RE, Liu H, Yao P, Petukhov PA, Bolton JL, Thatcher GR

Benzothiophene selective estrogen receptor modulators with modulated oxidative activity and receptor affinity.

J Med Chem. 2007 May 31;50(11):2682-92. Epub 2007 May 10.

PubMed ID
17489582 [ View in PubMed
]
Abstract

The regulation of estrogenic and antiestrogenic effects of selective estrogen receptor modulators (SERMs) is thought to underlie their clinical use. Most SERMs are polyaromatic phenols susceptible to oxidative metabolism to quinoids, which are proposed to be genotoxic. Conversely, the redox reactivity of SERMs may contribute to antioxidant and chemopreventive mechanisms, providing a new approach to improve the therapeutic properties of SERMs. An improved synthetic strategy was developed to generate a family of benzothiophene SERMs. Using computational modeling methods and measurements of antioxidant activity and estrogen receptor (ER) ligand binding, this SERM family was shown to provide both a range of ERalpha/ERbeta selectivity from 1.2- to 67-fold and a range of redox activity. Antioxidant activity was successfully modulated by varying a substituent remote from the OH group; the source of the antioxidant capacity. An efficient synthetic procedure is reported yielding benzothiophene SERMs wherein redox activity and ER affinity are modulated.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
RaloxifeneEstrogen receptor alphaIC 50 (nM)20.67.522Details
RaloxifeneEstrogen receptor betaIC 50 (nM)5577.522Details