ERa Selective SERMs

Aryl-Indoles Scientists at Merck described 2-aryl-indoles as ERa-selective SERMs [137]. HTS uncovered indole 101, which showed reasonable receptor affinity but very high ERa selectivity. However, 101 expressed agonism in an immature rat... 

Phenantrenes SignalGene reported on phenantrenes as SERM-type ligands for the ERs [180]. Most of the phenantrenes disclosed showed very low affinity for either ER, but dihydrophenantrene analog 143 showed reasonable ERa affinity (K, = 9 nM) and 22-fold ERa selectivity. 

The anti-estrogen, tamoxifen, is the most commonly used hormonal therapy for breast cancer and has demonstrated positive effects on the cardiovascular and skeletal systems of postmenopausal women but is associated with an increased risk of uterine cancer. Tamoxifen is described as a SERM, a selective estrogen receptor modulator with a tissue selective profile that is caused by the different distribution of the a- and /3-subtypes of the estrogen receptor (ERa and ER/3) that activate and inhibit transcription respectively (77). These selective effects have been ascribed to differential interactions with gene promotor elements and coregulatory proteins depending on whether the ERa interacts directly, or in a tethered manner with DNA (78). In uterine tissue, tamoxifen interacts with a specific coactivator, SRCl, that is abundant in uterine tissue. 

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