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Results for “Selective Estrogen Receptor Modulators”

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At least 379 records · Page 21Linked to original sources
PubMed2005

Selective estrogen receptor modulators in the ruthenocene series. Synthesis and biological behavior.

A series of ruthenocene derivatives, 1-[4-(O(CH(2))(n)()N(CH(3))(2))phenyl]-1-(4-hydroxyphenyl)-2-ruthenocenylbut-1-ene, with n = 2-5, based on the structure of the breast cancer drug tamoxifen has been prepared. These compounds were obtained, via a McMurry cross-coupling reaction, as a mixture of Z and E isomers that could not be separated by HPLC. The relative binding affinity values for estrogen receptor alpha (ERalpha) for n = 2 and 3 were very high (85 and 53%) and surpassed even that of hydroxytamoxifen (38.5%), the active metabolite of tamoxifen. Ruthenocene derivatives act as anti-estrogens as effective (n = 2) or slightly more effective (n = 3-5) than hydroxytamoxifen on ERalpha-positive breast cancer cell lines but, unlike ferrocifens, do not show antiproliferative effects on ERalpha-negative breast cancer cell lines. Electrochemical studies showed that the ruthenocifen radical cations are unstable, which may account for this behavior. Some of these compounds could be useful as radiopharmaceuticals for ERalpha-positive breast cancer tumors.

Antineoplastic Agents↗
PubMed1998

Estrogens and atherosclerosis: phytoestrogens and selective estrogen receptor modulators.

The development of atherosclerosis in animal models and the incidence of coronary heart disease in postmenopausal women are markedly reduced by estrogen treatment. Estrogen have acute beneficial effects on vascular reactivity and longer-term effects on critical steps in the pathogenesis of atherosclerosis. Phytoestrogens present in soybeans and other plant products are weak estrogens but appear to have potent beneficial effects on the arterial wall. The phytoestrogens have certain similarities to 'designer hormones' which are being developed to retain their beneficial effects on the cardiovascular system and the skeleton without having cancer promoting effects on the breast and endometrium.

Animals↗
PubMed1998

Reproductive endocrine and endometrial effects of raloxifene hydrochloride, a selective estrogen receptor modulator, in women with regular menstrual cycles.

Previous studies of raloxifene conducted in animal models and postmenopausal women have demonstrated antiestrogenic action on the endometrium. The purpose of this first study of raloxifene in women with normal menstrual cycles was to determine its reproductive endocrine and endometrial effects. In part I, raloxifene (400 mg) was administered for 5 days in the follicular, periovulatory, or luteal phase of the menstrual cycle (n = 12). In part II, women were randomized to receive raloxifene (100 or 200 mg) for 28 days beginning on day 3 of the cycle (n = 19). All women ovulated in both parts of the study. Raloxifene did not alter the length of the menstrual cycle or the day of the LH surge. A 5-day course of raloxifene administered in any phase of the cycle elevated FSH area under the curve (AUC) for the entire cycle and estradiol AUC for the second half of the cycle compared with those in control cycles. In part II, raloxifene also appeared to increase the FSH AUC and estradiol AUC. Raloxifene decreased the number of gland mitoses in follicular phase endometrial biopsies. Subtle effects suggestive of gland-stromal dysynchrony were noted in a limited number of the secretory phase endometrial biopsies. This study has demonstrated that 1) raloxifene does not prevent ovulation in women with normal menstrual cycles; 2) ovarian estrogen production will continue, and in some cases increase, in response to raloxifene; and 3) antiestrogenic effects of raloxifene on the endometrium are subtle in the endocrine milieu of normal to high circulating estradiol concentrations.

Adult↗
PubMed1999

[Raloxifene: a selective modulator of estrogen receptors].

It has been demonstrated that postmenopausal hypoestrogenia induces numerous complications including osteoporosis and increased risk of cardiovascular disease. Oral or transdermal administration of estrogens can reduce these risks, but induces adverse effects. Recently, raloxifene, a new molecule from the benzothiophene family, has been demonstrated to prevent postmenopausal bone loss. It does not induce endometrial stimulation, and recent studies show that it could reduce breast cancer incidence. Its mode of action, consisting of mixed agonist and antagonistic estrogenic actions on different organs and systems, allows to classify it into the selective estrogen receptor modulator (SERM) family. In this review article, we will describe the characteristics of the molecule, its mode of action and the potential indications of its clinical use.

Breast Neoplasms↗
PubMed2002

A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta.

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.

Crystallography, X-Ray↗
PubMed2001

Selective estrogen-receptor modulators in 2001.

Tamoxifen (Nolvadex), a selective estrogen-receptor modulator, or SERM, is currently the endocrine therapy of choice for all stages of hormone-responsive breast cancer. Only tamoxifen has been approved by the US Food and Drug Administration to reduce the incidence of breast cancer in high-risk women. Despite tamoxifen's antiestrogenic effects in breast tissue, it exhibits paradoxical estrogenic effects in other tissues in the body. These effects result in the maintenance of bone mineral density, but a three- to fourfold increase in endometrial cancer in postmenopausal women. Additionally, tamoxifen can result in troublesome hot flashes and serious thromboembolic events. For this reason, current research is focusing on new agents that may maintain the beneficial effects of tamoxifen while reducing its adverse effects. Raloxifene (Evista) is another SERM, approved for the prevention of osteoporosis in postmenopausal women and now being compared with tamoxifen in an ongoing breast cancer prevention trial. Like tamoxifen, raloxifene is associated with hot flashes and thromboembolic events, but its association with the risk of endometrial cancer is unknown. A number of new SERMs are in preclinical or clinical development in an attempt to improve upon the safety profile of tamoxifen. Additionally, selective aromatase inhibitors are being examined in the early breast cancer setting.

Breast Neoplasms↗
PubMed2003

Long-term toxicities of selective estrogen-receptor modulators and antiaromatase agents.

Published literature indicates that the selective estrogen-receptor modulators (SERMs) tamoxifen and raloxifene (Evista) have favorable effects on bone density, lipid profiles, and the incidence of second breast cancers, and unfavorable effects on the incidence of venous thrombosis and hot flushes. Tamoxifen increases the risk of endometrial cancer, but raloxifene does not. The effects of SERMs on sexual function and cognition are unclear. Because the selective antiaromatase agents are relatively new, the long-term effects of these agents on normal tissues are less well established. It appears that the nonsteroidal agents (anastrozole [Arimidex], letrozole [Femara]) and steroidal (exemestane [Aromasin]) antiaromatase agents may have different effects on normal tissues. Preliminary data demonstrate that anastrozole increases the risk of arthralgias and produces a decrease in bone density. In contrast, exemestane appears to favorably affect bone density and lipid profile, similar to tamoxifen and raloxifene. The incidence of contralateral breast cancer is decreased in women on adjuvant anastrozole, but data for the other antiaromatase agents are not yet available. Hot flushes have been reported with the use of selective aromatase inhibitors, but their incidence seems to be comparable to what is reported with SERMs. Antiaromatase agents do not appear to cause venous thrombosis. More information about the effects of the antiaromatase agents on normal tissue will become available as data from ongoing adjuvant and chemoprevention trials are reported. Clinically, we should be conscious of the differences between antiaromatase agents and SERMs and their impact on women's health.

Adult↗
PubMed2001

Silencing and reactivation of the selective estrogen receptor modulator-estrogen receptor alpha complex.

4-Hydroxytamoxifen (4-OHT), a selective estrogen receptor modulator, is an agonist at a transforming growth factor-alpha (TGF-alpha) target gene in situ in MDA-MB-231 human breast cancer cells stably transfected with wild-type human ERalpha. In contrast, raloxifene (Ral) is a complete antiestrogen silencing activation function (AF) 1 and AF2 in this system. A natural mutation D351YERalpha enhances 4-OHT agonist activity and changes Ral-like compounds from antagonists to partial agonists. We reasoned that: either the conformation of the Ral-D351YERalpha is altered, thereby reactivating AF2 in the ligand binding domain, or the change at amino acid 351 allosterically reactivates AF1 in the Ral-D351YERalpha complex. Unlike the estradiol-ERalpha complex, agonist activity of 4-OHT and raloxifene through ERalpha and D351YERalpha were not attributed to coactivator (such as SRC-1, AIB1) binding to the ligand binding domain. We conclude that the classic AF2 is not responsible for the agonist activities of 4-OHT-ERalpha, 4-OHT-D351YERalpha, and Ral-D351YERalpha. To address the role of AF1, stable transfectants of ERalpha or D351YERalpha with an AF1 deletion (D351deltaAF1, D351YdeltaAF1) were generated in MDA-MB-231 cells. Additionally, D538A/E542A/D545A triple mutations within helix 12 (D351-3m, D351Y3m) or the COOH-terminal 537 deletion (D351delta537) were tested. The agonist activities of 4-OHT and raloxifene were lost in these stable transfectants, but antiestrogenic action was retained. The reactivation of an estrogen-like property of the Ral-ERalpha complex through AF1 with the D351Y mutation illustrates a novel allosteric mechanism for the selective estrogen receptor modulator ERalpha complex.

Allosteric Regulation↗