Figure 21 Conformationally constrained raloxifene analogs.

intolerant to hydrophilic substitution. Phenanthridine (40) was determined to be an antagonist of MCF-7 proliferation in vitro (IC50 = 1 nmol L_and a partial estrogen antagonist in the immature rat model at oral doses of 1 and 10 mgkg _ 1, which is similar to the profile of tamoxifen. The compound also lowered serum cholesterol at oral doses of 0.1-10 mgkg "1.

Tetrahydrochrysene (THC) derivatives have previously been described as estrogen receptor ligands with interesting biological properties.92 For example, ¿¿-diethyl THC derivative (42: Figure 22), has been shown to be an agonist through ERa but an antagonist on ERb.93 Related saturated analogs containing a ¿¿-fused ring junction have recently been described.94 Interestingly, compounds lacking the basic side chain show some selectivity for binding to ERb, whereas compounds possessing the basic side chain are ERa-selective ligands. For example, tetrahydrobenzofluorene (43: RBA ERa = 38%; RBA ERb = 10%) and hexahydrochrysene (44: RBA ERa = 1.1%; RBA ERb = 0.06%) have increased affinity for ERa relative to ERb. Both 43 and 44 have been shown to possess interesting transactivation profiles. Compound 43 was demonstrated to be an antagonist on both ERa and ERb, whereas 44 was an antagonist on ERb but was a mixed agonist-antagonist through ERa. The higher affinity of 43 compared to 44 and its higher antagonistic character may be due to a more favorable orientation of the basic side, thus facilitating key contacts between the piperidine nitrogen and the receptor (Asp-354).

Recently, a SERM with improved selectivity for uterus and ovaries has been identified.95 This naphthalene sulfone-derived SERM (Figure 23) binds with high affinity to both estrogen receptors and is a potent inhibitor of MCF-7 cell proliferation (IC50 = 0.86 nmol L_ 1). The effects on uterine tissue were assessed at the in vitro level in Ishikawa cells in the presence (antagonism) and absence (agonism) of E2. In the antagonist mode, this SERM blocks the effects of 1 nmol L_ 1 E2 by >90% with an IC50 of 10.7 nmol L_ 1. The agonist activity was similar to that of 1 (29.0 + 3.7% over control versus 28.6 + 8.50% for 1) and significantly less than that of 4-hydroxytamoxifen (123 + 24%), a known uterine agonist. When tested in rodents, this compound proved to be a highly potent, orally active uterine antagonist with an ED50 of 0.07 mgkg_ 1 at blocking estrogen-induced uterine hypertrophy in immature, ovary-intact rats. Significantly, this analog is greater than fivefold more potent than raloxifene as a uterine antagonist. In addition, it does not have agonist properties in the uterus when administered to OVX rats for 4 days at all doses examined (0.01-10.0mgkg_ 1, data not shown) based on eosinophil peroxidase activity, a sensitive marker for determining the uterine agonist properties of SERMs.96 Long-term treatment (42 days) to OVX rats does not cause uterine weight gain.97 Taken together, the uterine data indicate that this SERM is a potent estrogen antagonist without significant agonist properties o


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