The onset of menopause has been associated with a reduction in endogenous estrogen levels that has been correlated with a variety of menopausal symptoms and an increased risk for osteoporosis and heart disease. Hormone replacement therapy successfully alleviates these symptoms, but concerns about hyperplastic estrogen action on breast and uterine tissue have been raised. Largely as a result of these issues, considerable research has been dedicated to the discovery of estrogens that act in a tissue selective fashion. Of particular interest was the 2-phenylindole compound, 5. Whereas it appears from inspection that the core template of the indole can function in a similar fashion as other selective estrogen stilbene-type cores, we postulated that the aliphatic, amine-containing side chain is too flexible to provide for optimal displacement of helix 12 upon binding. To that end, we decided to examine the effect of placing a rigidifying linker between the amine terminus and the indole nitrogen. To do this, we constructed a phenoxyethyl linker between the amine of the side chain and the N-1 position of the indole. In this way, the modified indoles have side chains that more closely resemble other selective estrogens already described. After various explorations around the core and side chain, we discovered ERA-923 6 and TSE-424 7, both novel, highly selective estrogens with particularly non-estrogenic profiles on rat uterine tissue. Compounds 6 and 7 were evaluated for their ability to displace [3H]17β-estradiol from estrogen receptor ligand binding domain constructs (human) of both the α- and β-receptors (ERα and ERβ). Both 6 and 7 show respectable affinity for both forms of the receptor, albeit with a slight preference for ERα. Compounds 6 and 7 were also evaluated for their functional estrogenic/antiestrogenic activity in an MCF-7 cell ERE-tk-luciferase (ERα mediated) assay. Since neither 6 nor 7 stimulate transcriptional activity in these cells, they were evaluated in the antagonist mode by competition with 10 pM 17β-estradiol. Only 6, 7, and 3 were potent antagonists in this assay; all having IC50s less than 5 nM. All compounds were tested in a 3-day immature rat uterine model. Both 6 and 7 showed no significant uterine stimulation when dosed alone. In the antagonist mode, 6 and 7 were able to completely inhibit the uterine wet weight increase effected by 4. In a 6-week ovariectomized rat study, 7 was examined for its ability to prevent bone loss. 7 protected against bone loss in the proximal tibia and reached significant efficacy at a dose of 0.3 mg/kg per day. Additionally, 7 reduced total cholesterol with maximal efficacy (approximately 50%) at just 0.1 mg/kg per day while demonstrating no statistically significant effect on uterine wet weight in any of the treated animal groups. From the data presented, side chain structure is an important determinant of selective estrogen action. Whereas the indole 5 displayed considerably reduced antiestrogen efficacy in an MCF-7 ERE-tk luciferase assay as well as some estrogen agonist activity in a 3-day immature rat uterine assay, compounds 6 and 7 behaved as potent antagonists in these assays. We believe that for the amine-containing side chains it is optimal to have the phenoxy group present to rigidify this portion of the molecule. Both 6 and 7 display very attractive selective estrogen profiles. Due to functional differences between the two compounds it was decided that 7 should be advanced for treatment of postmenopausal osteoporosis. Whereas 7 was very efficacious at protecting against bone loss and reducing total cholesterol in the ovariectomized rat model of osteopenia, 6 was a very potent and efficacious antiestrogen in various in vivo MCF-7 xenograft models. Currently, 6 is in phase II clinical trials for the treatment of hormone-dependent metastatic breast cancer, and 7 has completed phase II clinical trials for the prevention and treatment of postmenopausal osteoporosis.