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Results for “Estrogen Receptor Modulators”

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PubMed2001

Mechanism of action and preclinical profile of raloxifene, a selective estrogen receptor modulation.

Raloxifene possesses a complex pharmacology with tissue-selective estrogen agonist and antagonist effects. At the center of these effects resides the high affinity interaction of raloxifene with the ER. The ability of raloxifene to compete with estrogen for ER binding accounts for the estrogen antagonist effects of raloxifene in uterine and mammary tissue. Since the precise mechanism for the agonist effect of estrogen on the skeleton remains uncertain, it is difficult to unequivocally cite a single estrogen-like mechanism for raloxifene in bone. However, multiple lines of evidence clearly indicate that the estrogen agonist effect of raloxifene on bone is also mediated via an interaction with ER. The data showing non-additivity of raloxifene and estrogen effects in bone, and those showing the requirement for a pituitary hormone in the anti-estrogenic action of raloxifene and estrogen are particularly important. Thus, global evaluation of the similarities and parallel responses of raloxifene and estrogen in bone and the cardiovascular system, as summarized above, strongly support a similar mechanistic basis for the agonist effects of these agents on the skeleton.

Animals↗
PubMed1996

The effect of a selective estrogen receptor modulator on the progression of spontaneous autoimmune disease in MRL lpr/lpr mice.

The MRL lpr/lpr mouse strain is an animal model for the autoimmune disorder systemic lupus erythematosus (SLE). Pathologic changes in the mice include a severe proliferative glomerulonephritis, lymph node and spleen enlargement, increase in autoantibody titers, and shortened life spans. In the present investigation, female MRL lpr/lpr mice have been dosed po daily for 7 months with the selective estrogen receptor modulator (SERM) LY139478 (4 mg/kg) or 17alpha-ethinylestradiol (EE2, 1 mg/kg) and compared to vehicle control animals. The LY139478 group had an increase in survival (73% survival at 7 months, P = 0.02) but the EE2-treated animals did not (53% survival at 7 months, P = 0.4) when compared to the control group (32% survival at 7 months). Although there were no reductions in autoantibody levels as determined by anti-DNA antibody ELISA, histological analysis of kidney tissue indicated that both LY139478 and EE2 mitigated the progression of glomerular nephritis which was evident in the controls. In contrast, there were no significant differences in lymph node size although the LY139478 and EE2 groups retained a well-defined sinusoidal region. Finally, flow cytometric analysis documented that thymuses from animals treated for 7 months with LY139478 but not with EE2 contained predominantly CD4+/CD+ T cells consistent with a normal thymic phenotype observed in non-MRL lpr/lpr mouse strains. These studies demonstrate that SERMs may be potentially useful for the treatment of autoimmune disorders.

Animals↗
PubMed2003

Estrogen receptor modulators: relationships of ligand structure, receptor affinity and functional activity.

The estrogen receptor is a regulator of a wide range of physiological functions, including the female reproductive system, in addition to bone, cardiovascular and CNS function. ER ligands have been approved for the treatment of menopausal symptoms, breast cancer and osteoporosis, however the search continues for new modulators of ER function with improved properties. Progress in medicinal chemistry programs has resulted in the identification of structurally diverse molecules with unique biological properties. Recent advances in the design and synthesis of these non-steroidal and steroidal estrogen receptor ligands is reviewed. The relationship between the structural features of the ligand and receptor function is also discussed.

Animals↗
PubMed2005

Selective estrogen receptor modulators to prevent treatment-related osteoporosis.

The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, which is a leading cause of osteoporosis in men. Consistent with this observation, GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. GnRH agonists markedly decrease serum levels of both testosterone and estrogen. Estrogens play a central role in homeostasis of the normal male skeleton, and the available evidence suggests that estrogen deficiency rather than testosterone deficiency accounts for the adverse skeletal effects of GnRH agonists. The central role of estrogens in male bone metabolism provides a strong rationale to evaluate selective estrogen receptor modulators for prevention of treatment-related osteoporosis in men with prostate cancer. Preliminary evidence suggests that both raloxifene and toremifene increase bone mineral density in GnRH agonist-treated men. An ongoing pivotal study will evaluate the effects of toremifene on fractures and other complications of GnRH agonists in men with prostate cancer.

Journal Article↗
PubMed2005

The molecular pharmacology of estrogen receptor modulators: implications for the treatment of breast cancer.

In addition to physiologic activities in the reproductive, skeletal, and central nervous systems, estrogens have been shown to play important roles in the aberrant cell proliferation observed in breast and reproductive tract cancers. Not surprisingly, pharmaceuticals that target different steps in the estrogen signal transduction pathway have found widespread use in the treatment of a wide variety of estrogen-linked disorders. The goal of this review is to outline what is known about the molecular pharmacology of the estrogen receptor and discuss how this information can be used to guide selection of drugs for a particular therapeutic application, and identify new targets where pharmaceutical exploitation could yield novel therapeutics.

Antineoplastic Agents, Hormonal↗
PubMed2005

A pharmacophore-based evolutionary approach for screening selective estrogen receptor modulators.

We developed a pharmacophore-based evolutionary approach for virtual screening. This tool, termed the Generic Evolutionary Method for molecular DOCKing (GEMDOCK), combines an evolutionary approach with a new pharmacophore-based scoring function. The former integrates discrete and continuous global search strategies with local search strategies to expedite convergence. The latter, integrating an empirical-based energy function and pharmacological preferences (binding-site pharmacological interactions and ligand preferences), simultaneously serves as the scoring function for both molecular docking and postdocking analyses to improve screening accuracy. We apply pharmacological interaction preferences to select the ligands that form pharmacological interactions with target proteins, and use the ligand preferences to eliminate the ligands that violate the electrostatic or hydrophilic constraints. We assessed the accuracy of our approach using human estrogen receptor (ER) and a ligand database from the comparative studies of Bissantz et al. (J Med Chem 2000;43:4759-4767). Using GEMDOCK, the average goodness-of-hit (GH) score was 0.83 and the average false-positive rate was 0.13% for ER antagonists, and the average GH score was 0.48 and the average false-positive rate was 0.75% for ER agonists. The performance of GEMDOCK was superior to competing methods such as GOLD and DOCK. We found that our pharmacophore-based scoring function indeed was able to reduce the number of false positives; moreover, the resulting pharmacological interactions at the binding site, as well as ligand preferences, were important to the screening accuracy of our experiments. These results suggest that GEMDOCK constitutes a robust tool for virtual database screening.

Binding Sites↗
PubMed1997

Hypocholesterolemic activity of raloxifene (LY139481): pharmacological characterization as a selective estrogen receptor modulator.

After once-daily oral dosing in ovariectomized rats, raloxifene (LY139481) hydrochloride produced dose- and time-dependent reductions in serum cholesterol and high-density lipoprotein-cholesterol. Paired-feeding studies demonstrated that effects of raloxifene on serum lipids were not secondary to effects on food consumption. Maximal reductions in serum cholesterol occurred within 4 days of raloxifene administration or sooner, depending on the administered dose. The ED50 for 50% reduction in serum cholesterol by raloxifene was 0.13 +/- 0.04 mg/kg/day (mean +/- S.E.M., n = 17); maximal cholesterol reduction by raloxifene (68%) was significantly less than that produced by estrogen (17 alpha-ethinylestradiol; 89%) after 4 to 7 days of daily dosing. Dose-response curves for cholesterol lowering by raloxifene were generated in the presence of varying doses of 17 alpha-ethinylestradiol; two-way analysis of variance revealed significant interactions between estrogen and raloxifene with respect to cholesterol lowering (P < .001). Furthermore, a high dose of raloxifene (10 mg/kg/day) prevented further reduction of serum cholesterol by estrogen (1-100 micrograms/kg/ day) beyond that produced by raloxifene alone. For a series of closely related structural analogs of raloxifene, log(ED50) values for cholesterol lowering were highly correlated with log(relative binding affinity) for the estrogen receptor (r = 0.93; P < .0001). Thus, cholesterol lowering by raloxifene in ovariectomized rats is mediated primarily via partial agonist effects at estrogen receptors. Taken together with previous observations in uterine tissue of estrogen antagonism by raloxifene in the absence of significant agonism, the present findings support the classification of raloxifene as a selective estrogen receptor modulator.

Animals↗
PubMed2000

Selective estrogen receptor modulators (SERMs): effects on multiple organ systems.

SERMs represent a structurally diverse group of compounds which interact with the estrogen receptor but which elicit agonist or antagonist activity depending on the organ system and physiological context. Evaluation of the actions of these compounds has led researchers to a fuller understanding not only of the antiestrogens but also of steroid signaling in general. Based on their evolving clinical profiles, SERMs have the potential to address long-term health maintenance needs of women in their non-reproductive years.

Animals↗
PubMed2005

Activity of estradiol and selective estrogen receptor modulators in the mouse N20.1 oligodendrocyte/astrocytes cell line.

OBJECTIVE: The mechanism through which estrogen exerts its neuroprotective and anti-neurodegenerative effects in the central nervous system is poorly understood. Human glial cells are implicated in the pathogenesis of Alzheimer's disease and have both alpha and beta estrogen receptors (ER). We developed a glial cell model for ER function using the N20.1 mouse oligodendroglial cell line to evaluate the response of ERalpha and ERbeta to estradiol (E2), a raloxifene analog LY117018 (LY) and 4-hydroxytamoxifen (4OHT). DESIGN: We tested the ability of exogenous ER to activate transcription in response to ligands (100 nM) using the glial cell line N20.1 in a transient cotransfection assay with an ERalpha or ERbeta expression vector, an ERE-driven reporter and a Renilla luciferase transfection control. RESULTS: Endogenous ER was not detected in the N20.1 cells by Western immunoblotting. E2 stimulated both ERalpha and ERbeta on both ERE- and AP-1 driven promoters. The transcription stimulation by E2 in the ERalpha and ERbeta through the AP-1driven promoter, though significant, was not of the same magnitude as the stimulation of the ERalpha through the ERE-driven promoter. 4OHT and LY did not show significant transcriptional activation of either the ERalpha or ERbeta, through either the ERE or AP-1 driven promoters. LY, at a 10-fold higher concentration than E2, showed a difference in its antagonist activity on the ERbeta through the AP-1 pathway when compared with the ERE- driven promoter, demonstrating not only promoter specificity, but also receptor specificity. CONCLUSIONS: This is the first description of the activity of 4OHT and LY on estrogen receptors in glia.

Animals↗
PubMed2003

Simple and efficient production of (Z)-4-hydroxytamoxifen, a potent estrogen receptor modulator.

A McMurry coupling reaction and selective crystallization were used to develop a simple and efficient two-step synthesis of (Z)-4-hydroxytamoxifen (2a). This compound is an active metabolite of tamoxifen, a selective estrogen receptor (ER) modulator widely used to treat breast cancer. The synthesis employed 1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-ene (1) as a useful building block.

Binding, Competitive↗
PubMed1999

The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens.

The human estrogen receptor alpha (ERalpha) and the recently identified ERbeta share a high degree of amino acid homology; however, there are significant differences in regions of these receptors that would be expected to influence transcriptional activity. Consequently, we compared the mechanism(s) by which these receptors regulate target gene transcription, and evaluated the cellular consequences of coexpression of both ER subtypes. Previously, it has been determined that ERalpha contains two distinct activation domains, ERalpha-AF-1 and ERalpha-AF-2, whose transcriptional activity is influenced by cell and promoter context. We determined that ERbeta, like ERalpha, contains a functional AF-2, however, the ERbeta-AF-2 domain functions independently within the receptor. Of additional significance was the finding that ERbeta does not contain a strong AF-1 within its amino-terminus but, rather, contains a repressor domain that when removed, increases the overall transcriptional activity of the receptor. The importance of these findings was revealed when it was determined that ERbeta functions as a transdominant inhibitor of ERalpha transcriptional activity at subsaturating hormone levels and that ERbeta decreases overall cellular sensitivity to estradiol. Additionally, the partial agonist activity of tamoxifen manifest through ERalpha in some contexts was completely abolished upon coexpression of ERbeta. In probing the mechanisms underlying ERbeta-mediated repression of ERalpha transcriptional activity we have determined that 1) ERalpha and ERbeta can form heterodimers within target cells; and 2) ERbeta interacts with target gene promoters in a ligand-independent manner. Cumulatively, these data indicate that one role of ERbeta is to modulate ERalpha transcriptional activity, and thus the relative expression level of the two isoforms will be a key determinant of cellular responses to agonists and antagonists.

Carcinoma, Hepatocellular↗
PubMed2000

Selective estrogen receptor modulators and postmenopausal health.

SERMs are a class of drugs with mixed estrogen agonist/antagonist effects that have great potential at targeting changes seen in the postmenopausal period. Raloxifene is effective in preventing bone loss and may prevent fractures in postmenopausal osteoporosis. It induces changes in lipoprotein concentrations that should be cardioprotective. It has no stimulatory effect on the uterus and is well tolerated. Raloxifene is an attractive alternative to HRT in preventing postmenopausal bone loss, especially for women that are more concerned about the risk of breast cancer or vaginal bleeding. Unanswered questions include raloxifene's effect on fracture incidence, cardiac events, and dementia; long-term safety data are also needed. Its potential role in the primary prevention of breast cancer also needs large, long-term studies. Tamoxifen has been used traditionally as adjuvant therapy for breast cancer, but new data indicate that it is effective in the primary prevention of breast cancer in women at increased risk. Its effects on bone and lipoproteins are attractive complementary effects when used in the subset of women at increased risk for breast cancer. New generations of SERMs are being developed that may have more potent estrogen agonist effects on bone and cardiovascular disease, or more potent antiestrogen effects, especially at the breast. There will likely be a selection of SERMs available, and the choice of SERM for a woman will be tailored to her specific issues and risk profile.

Breast Neoplasms↗
PubMed2006

Derivatives of Z-bisdehydrodoisynolic acid provide a new description of the binding-activity paradox and selective estrogen receptor modulator activity.

Z-Bisdehydrodoisynolic acid [(+/-)-Z-BDDA], an estrogenic carboxylic acid, is highly active in vivo yet binds poorly to estrogen receptors (ERs). Studies of Z-BDDA and its enantiomers demonstrate therapeutic potential as selective ER modulators; however, the activity vs. binding paradox has remained. One possible explanation is that the carboxylic acid group of Z-BDDA may be modified in vivo to an ester or amide. Synthesis of these derivatives showed the relative binding affinity (RBA) of the methyl ester for ERalpha and ERbeta was increased approximately 14- and 20-fold, respectively, relative to the parent compound. Yet, this increased affinity did not result in increased reporter gene expression. In contrast, the amide showed an unexpected approximately 4-fold decrease in RBA to both ERs compared with the parent. The relationship among the RBAs of ester, acid, and amide is consistent with their predicted polarity, suggesting the carboxylic acid, and not the carboxylate of BDDA, binds to ERs. Studies at pH 6.5, 7.4, and 8.0 were consistent with a simple acid-base equilibrium model, with BDDA binding as the undissociated acid and with affinity equal to or exceeding that of estradiol, consistent with high in vivo potency. Furthermore, the alcohol BDD-OH also demonstrated high affinity and increased activity in gene expression assays. In addition to suggesting a resolution to the decades-old binding/activity paradox, these studies may provide a direction for definitive in vivo metabolic and pharmacokinetic studies and provide additional insight into the chemical and metabolic determinants of BBDA's unique tissue selectivity and selective ER modulator activities.

Alcohols↗