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A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta. 2002
Brad R Henke, and
Thomas G Consler, and
Ning Go, and
Ron L Hale, and
Dana R Hohman, and
Stacey A Jones, and
Amy T Lu, and
Linda B Moore, and
John T Moore, and
Lisa A Orband-Miller, and
R Graham Robinett, and
Jean Shearin, and
Paul K Spearing, and
Eugene L Stewart, and
Philip S Turnbull, and
Susan L Weaver, and
Shawn P Williams, and
G Bruce Wisely, and
Millard H Lambert
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA. brh14990@gsk.com
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.
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