A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta.

Article Details

Citation

Henke BR, Consler TG, Go N, Hale RL, Hohman DR, Jones SA, Lu AT, Moore LB, Moore JT, Orband-Miller LA, Robinett RG, Shearin J, Spearing PK, Stewart EL, Turnbull PS, Weaver SL, Williams SP, Wisely GB, Lambert MH

A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta.

J Med Chem. 2002 Dec 5;45(25):5492-505.

PubMed ID
12459017 [ View in PubMed
]
Abstract

A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
4-(2-{[4-{[3-(4-Chlorophenyl)Propyl]Sulfanyl}-6-(1-Piperazinyl)-1,3,5-Triazin-2-Yl]Amino}Ethyl)PhenolEstrogen receptor betaIC 50 (nM)6N/AN/ADetails
4-(2-{[4-{[3-(4-Chlorophenyl)Propyl]Sulfanyl}-6-(1-Piperazinyl)-1,3,5-Triazin-2-Yl]Amino}Ethyl)PhenolEstrogen receptor betaKi (nM)15N/AN/ADetails
EstradiolEstrogen receptor alphaEC 50 (nM)0.07N/AN/ADetails
EstradiolEstrogen receptor betaEC 50 (nM)0.8N/AN/ADetails
RaloxifeneEstrogen receptor alphaIC 50 (nM)0.7N/AN/ADetails
RaloxifeneEstrogen receptor betaIC 50 (nM)15N/AN/ADetails