. Author manuscript; available in PMC: 2011 Apr 22.

Published in final edited form as: J Med Chem. 2010 Apr 22;53(8):3320–3329. doi: 10.1021/jm100047k

Table 1. Estrogen Receptor Binding Assay.

The ERα and ERβ binding affinities of SERDs with the triarylethylene (TAE), cyclofenil (CF) and bicyclononane (BN) core, and with the acrylic acid substituent are presented in the top part of (Table 1a). Some individual variants with the bicyclononane core are presented in the lower part of the (Table 1b).

a. Structure and Binding Affinity of Basic TAE, CF, and BN Systems

	Triarylethylene (TAE)				Cyclofenil (CN)				Bicyclononane (BN)



R	lignad	RBA^a ERα	RBA^a ERβ	β/α^b	lignad	RBA^a ERα	RBA^a ERβ	β/α^b	lignad	RBA^a ERα	RBA^a ERβ	β/α^b

	TAE	377 ± 106	238 ± 48	0.6	CF, 2	68 ± 18	334 ± 54	4.9	BN, 3	513 ± 17	301 ± 54	0.6
	4^c,^d	20.3 ± 6	28.3 ± 7	1.4	42^c	2.1 ± 5	11.3 ± 3	5.4	17^c	17.7 ± 4	25.9 ± 5	1.5
	4’^c	3.6 ± 1	4.2 ± 0.6	1.2	--	--	--	--	--	--	--	--
	--	--	--	--	44^c	0.63 ± 0.1	1.9 ± 0.6	3.0	15^c	3.6 ± 1	3.1 ± 0.3	0.9
	--	--	--	--	43^c	8.2 ± 0.5	28.8 ± 3	3.5	34^c	52.0 ± 6	89.1 ± 9	1.7
b. The ERα and ERβ binding affinity of other ligands with a bicyclononane core


R’	R	ligand	RBA^a ERα	RBA^a ERβ	β/α^b

-H	-OH	46	0.14 ± 0.02	0.30 ± 0.06	2.1
-O-CH₂-CO₂H	-O-CH₂-CO₂H	12	0.26 ± 0.05	0.40 ± 0.05	1.5
-OH	-O-(CH₂)₅-CO₂Et	29	15.2	30.8	2.0
-OH		26^c	7.5 ± 1	7.7 ± 0.7	1.0
-OH	-OSO₂CF₃	11	4.2 ± 1	8.9 ± 0.7	2.1

Relative binding affinity (RBA) values are determined by competitive radiometric binding assays and are expressed as IC₅₀^[estradiol] / IC₅₀^[compound] × 100 (RBA, estradiol = 100). In these assays the K_d for estradiol is 0.2 nM for ERα and 0.5 nM for ERβ.

For each value, the β/α ratio is calculated such that the ratio is >1 for compounds having higher affinity on ERβ than on ERα.

Compounds selected for further studies are indicated by a bold underline.

This compound, GW-7604 (4), exists as a mixture of E and Z isomers. See Figure 1.