A New Series of Estrogen Receptor Modulators That Display Selectivity for Estrogen Receptor β

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Abstract
A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERβ subtype are reported. Compound 1, which displayed modest potency and selectivity for ERβ vs ERα, was identified via high-throughput screening utilizing an ERβ 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 ERβ with potencies in the 10−30 nM range. These compounds profile as full antagonists at ERβ and weak partial agonists at ERα in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERβ 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 ERβ subtype.