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PubMed2003

Advances in the science of estrogen receptor modulation.

This work details recent advances in the science of estrogen receptor (ER) modulation, with emphasis on the discovery of novel ligands for the ER ligand binding domain (LBD). A detailed examination of structural studies of the ERs is presented with analysis of the impact of such works on contemporary ligand design and the molecular pharmacology of the ER. The various classes of ER modulators are discussed on the basis of stuctural similarities including selective estrogen receptor modulators (SERMs) and 'pure' non-steroidal antiestrogens. Additionally we review the emergence of a novel selective class of modulator which we have termed the selective estrogen receptor subtype modulators (SERSMs) and, in a departure from LBD strategies we examine the discovery of novel peptide inhibitors of the ER which inhibit transcriptional activiation of agonist liganded receptor through interaction with coactivator recruitment proteins, and offer unique insight to the mechanism of action of all classes of ER modulators. Through examination of patent and classical literature we present a thorough and informative cross-section of the contemporary state of the art in this exciting field of pharmaceutical research.

Animals↗
PubMed1999

Selective estrogen receptor modulators: tissue selectivity and differential uterine effects.

Selective estrogen receptor modulators (SERMs) are compounds that bind to estrogen receptors and produce estrogen-like (agonist) effects in some tissues and estrogen-blocking (antagonist) effects in other tissues. One of the goals of SERM research has been to develop compounds that provide the potential benefits of estrogen in the skeleton and cardiovascular system, but avoid the negative effects of estrogen in other tissues. Estrogen therapy has been consistently associated with endometrial stimulation, including glandular proliferation, hyperplasia and cancer. In contrast, the presence or degree of endometrial stimulation observed with SERMs varies by compound. The purpose of this review is to differentiate the endometrial effects of compounds that display a SERM-like profile. Molecular mechanisms involving SERM binding to estrogen receptors, preclinical uterine effects in both tissue culture and animal models, and endometrial findings in clinical experience are discussed. There are several SERMs commercially available or in development. The favorable safety profile of raloxifene in the uterus differentiates it from the others. Future SERM development will continue to focus on finding compounds that exhibit minimal endometrial stimulation.

Animals↗
PubMed1998

Selective estrogen receptor modulators (SERMs).

Naturally occurring estrogens, such as 17 beta-estradiol and estrone, have traditionally been thought to play a central role in the development and maintenance of the female reproductive system and secondary sexual characteristics. In recent years, their beneficial effects on the skeleton, the cardiovascular system, and the central nervous system, as well as the cancer risks associated with long term exposure have also been recognized. The widespread use of "antiestrogens" such as tamoxifen for the prevention and treatment of breast cancer has revealed that such compounds, while functioning as estrogen antagonists in mammary tissue, actually mimic the effects of estrogen in other tissues. The search for more selective agents has led to the development of raloxifene, a Selective Estrogen Receptor Modulator, which functions as an estrogen antagonist in the breast and uterus and as an estrogen agonist in the skeleton and cardiovascular system. Recent progress in the development of SERMs is the subject of this review, with an emphasis on structure activity relationships and on their effects in non-traditional target tissues.

Animals↗
PubMed1997

Selective estrogen receptor modulators and postmenopausal women's health.

Selective estrogen receptor modulators represent an alternative approach to the use of estrogen replacement therapy or hormone replacement therapy for decreasing postmenopausal bone loss, as well as for reducing the incidence of serious cardiovascular disease in this population. Of particular interest is raloxifene, a benzothiophene compound, which binds with high affinity to the estrogen receptor and produces effects similar to estrogen on the skeleton and cardiovascular system but behaves as a complete estrogen antagonist in the uterus and the breast. The pharmacologic profile of raloxifene, a discussion of a possible mechanism of action, and the potential role of this drug in women's postmenopausal health are the subjects of this review.

Aged↗
PubMed2000

Molecular mechanisms of selective estrogen receptor modulator (SERM) action.

In females, estrogens play a key role in reproduction and have beneficial effects on the skeletal, cardiovascular, and central nervous systems. Most estrogenic responses are mediated by estrogen receptors (ERs), either ER alpha or ER beta, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues act like estrogens, but block estrogen action in others. Thus, SERMs may exhibit an agonistic or antagonistic biocharacter depending on the context in which their activity is examined. For example, the SERMs tamoxifen and raloxifene both exhibit ER antagonist activity in breast and agonist activity in bone, but only tamoxifen manifests agonist activity in the uterus. Numerous studies have examined the molecular basis for SERM selectivity. Collectively they indicate that different ER ligands induce distinct structural changes in the receptor that influence its ability to interact with other proteins (e.g., coactivators or corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and of its target gene promoter affect SERM biocharacter. Taken together, SERM selectivity reflects the diversity of ER forms and coregulators, cell type differences in their expression, and the diversity of ER target genes. This model provides a basis for understanding the molecular mechanisms of SERM action, and should help identify new SERMs with enhanced tissue or target gene selectivity.

Humans↗
PubMed1999

Selective estrogen receptor modulators and phytoestrogens: new therapies for the postmenopausal women.

Estrogen deficiency in the postmenopausal woman results in numerous symptomatic and asymptomatic manifestations, including vasomotor symptoms, osteoporosis, heart disease, bladder and vaginal symptoms, and cardiovascular disease. Estrogen replacement therapy is associated with amelioration of these problems but has attendant risks. A newer class of drugs, the selective estrogen receptor modulators, provides both estrogen agonist and antagonist properties, depending on the target tissue. This article discusses the mechanism by which selective estrogen receptor modulators may vary in their end-organ effects and reviews the clinical studies associated with these compounds. Phytoestrogens are widely used in the United States, but little information is available regarding their potential long-term effects.

Aged↗
PubMed2000

Raloxifene: A selective estrogen receptor modulator (SERM) with multiple target system effects.

Selective estrogen receptor modulators (SERMs) exhibit a pharmacologic profile characterized by estrogen agonist activity in some tissues with estrogen antagonist activity in other tissues. These compounds were initially called "antiestrogens," but it was subsequently recognized that this inadequately described their spectrum of activities. The first widely used SERM, tamoxifen, has estrogen antagonist activity in breast tissue but shows estrogen-like activity in other tissues. Raloxifene is another SERM in clinical use, and it was developed to avoid some of the undesirable estrogen agonist actions of other SERMs to improve the drug safety profile. Raloxifene has been introduced for clinical use in treatment and prevention of postmenopausal osteoporosis. This review will explore the preclinical and clinical pharmacology of raloxifene, and compare it to other SERMs currently available for clinical use.

Bone and Bones↗
PubMed2005

[Effects of estrogen and selective estrogen receptor modulators on osteoporosis].

Evidence indicates that estrogen and raloxifene hydrochloride, a selective estrogen receptor modulator, prevent bone loss and reduce the risk of bone fractures in postmenopausal women. However, recent reports indicate that the health risks associated with the use of estrogen, which include breast cancer and coronary heart disease (CHD), exceed the benefits. In contrast, raloxifene is associated with a lower incidence of breast cancer and is not associated with CHD. Therefore, the use of raloxifene is preferable for the prevention and treatment of osteoporosis in postmenopausal patients.

Breast Neoplasms↗
PubMed2002

Effects of selective estrogen receptor modulators (SERMs) on coactivator nuclear receptor (NR) box binding to estrogen receptors.

Coactivators are required for activation of target genes by nuclear receptors. A well-studied class of coactivators, the p160 proteins, use short nuclear receptor interaction domains (NR boxes) to bind to the activated ligand-binding domain of a nuclear receptor. To investigate how selective estrogen receptor modulators (SERMs) affect NR box recruitment, we compared the recruitment of p160 NR box peptides to the estrogen receptor (ER)alpha and ER beta in the presence of 17beta-estradiol (E2), 4-OH tamoxifen (4-OH Tam), LY 117018 (a raloxifene analog), and ICI 182780 (ICI, an ER antagonist). Our coactivator interaction assay utilizes time-resolved fluorescence technology to assess the binding of the 10 NR boxes derived from the three known p160 coactivators (SRC-1, -2, -3) to the ER subtypes in the presence of each ligand. The SERMs we studied did not increase NR box binding to either ER alpha or ER beta, but instead were potent antagonists decreasing estradiol-dependent NR box binding. We also demonstrated inverse agonism for all of the SERMs tested as they dose-dependently decreased hormone-independent NR box binding to ER beta. Therefore, the SERMs studied behave as antagonists of ER alpha and ER beta NR box binding and do not increase coactivator NR box binding to either ER subtype. In addition, we examined the preference of E2-bound ER alpha and ER beta for various naturally occurring NR boxes including the 10 SRC boxes as well as the motifs from PGC-1, TRBP, TRAP220, and CBP. Interestingly, a clear preferential pattern of interaction was noted that was receptor specific.

Amino Acid Sequence↗
PubMed2003

Selective estrogen receptor modulators.

Because of recent concerns about the long-term risks of estrogen replacement therapy in postmenopausal women, there is growing interest in a group of compounds known as selective estrogen receptor modulators (SERMs). The SERMs bind to estrogen receptors and have tissue-specific effects that allow them to function as estrogen agonists in some tissues and estrogen antagonists in other tissues. There are four SERMs currently marketed in the United States. These include the triphenylethylenes--clomiphene citrate (Clomid), tamoxifen, and toremifene--and the benzothiophene, raloxifene. Clomid is used primarily in the treatment of infertility. Tamoxifen is indicated for the treatment and prevention of breast cancer. It has an estrogen antagonist effect on breast tissue, but an estrogen-like effect on lipids, bone, and the endometrium. Toremifene has an antagonist/agonist profile similar to that of tamoxifen. Raloxifene is approved for the prevention of osteoporosis in postmenopausal women. It is thought to be an estrogen antagonist on the uterus and breast tissues and an estrogen agonist with respect to bone and serum lipids.

Bone and Bones↗
PubMed2004

Lead identification of a potent benzopyranone selective estrogen receptor modulator.

Starting from a phenol screening hit (6), three series of benzopyranone selective estrogen receptor modulators (SERMs) have been designed, synthesized, and analyzed for both estrogen receptor alpha binding affinity and in vitro activity in two cell assays. The lead compound identified, SP500263 (13), was more potent than raloxifene and tamoxifen in a cell-based assay measuring inhibition of interleukin-6 release.

Animals↗
PubMed2004

Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in male rats.

BACKGROUND: Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) with greater than 100-fold selectivity against all other steroid receptors and is a potentially superior treatment for postmenopausal osteoporosis. The purpose of this study was to evaluate the effects of lasofoxifene on male reproduction in rats in light of the known effects of estrogen modulating compounds on male reproductive ability. METHODS: Lasofoxifene was administered to adult male rats at doses of 0.1, 1, 10, and 100 mg/kg for 66-70 consecutive days. After 28 days of dosing, male rats were cohabited with untreated female rats. Female rats were euthanized on gestation day 14 and a uterine examination was carried out for evaluation of reproductive parameters and embryo viability. Male rats were euthanized after 66-70 days of dosing and epididymal sperm motility and concentration were assayed. The testes, epididymides, prostate, and seminal vesicles were weighed and microscopically examined. RESULTS: The duration of cohabitation was increased for 100 mg/kg males by 0.7 days. The number of males copulating and the number of implantation sites produced per copulation were reduced in the 10 and 100 mg/kg groups. Weights of the seminal vesicles and epididymides were reduced for all groups, although the testes weight and epididymal sperm motility and concentration were not affected by treatment. There were no microscopic findings in the male reproductive tissues. CONCLUSION: The changes in male fertility and reproductive tissue weights after exposure to lasofoxifene are consistent with those previously described for estrogen receptor-modulating compounds.

Animals↗
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

Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands.

As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301)(-)(553)/C-->S triple mutant was solved to 2.28 A. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD(301)(-)(553)/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.

Administration, Oral↗
PubMed2004

Selective estrogen receptor modulation: concept and consequences in cancer.

Extended exposure to the selective estrogen receptor modulators (SERMs) such as raloxifene to prevent osteoporosis and tamoxifen or the aromatase inhibitors to treat or prevent breast cancer are established therapeutic strategies. However, there are now clearly defined consequences of exhaustive antihormonal therapy in breast cancer. Ultimately, drug resistance to SERMs and aromatase inhibitors enhances cancer cell survival but a paradoxical supersensitivity to estrogen action develops that causes cancer cell apoptosis. The future exploitation of these novel data will allow selective killing of cancer with fewer side effects for patients.

Apoptosis↗
PubMed2002

Molecular simulation of interaction between estrogen receptor and selective estrogen receptor modulators.

AIM: To study the mechanism of interaction between a series of potent racemic selective estrogen receptor modulators (SERM) and estrogen receptors (ER). METHODS: Active conformations of these conformationally restricted raloxifene analogues in binding pocket were determined by molecular mechanics. The interactive energies between ligand and receptor were calculated by docking program. RESULTS: Both R and S configurations of these SERM were accommodated by the binding pocket of ER. The hydroxy group of compounds forms hydrogen bonds with amino acid residues of ER and the phenolic group mimics the A ring of estradiol. The most potential compounds were those with two hydroxy groups and accommodated by binding pocket in S configuration with phenolic group at C(16) imitating A ring of estradiol. CONCLUSION: Chiral center conferred little effect on the binding affinity of these conformationally restricted raloxifene analogues. The hydroxy group(s) play(s) a critical role to the orientation of compounds in active pocket of ER and the binding between ligand and receptor.

Binding Sites↗
PubMed2004

[Selective estrogen receptor modulators: mechanisms of action and their tissue selectivity].

The SERMs (Selective Estrogen Receptor Modulators) exert selective agonistic or antagonistic effects on various estrogen target tissues. Conformational change of SERM-bound Estrogen Receptor (ER) and tissue specific expression patterns of transcription co-factors have been well investigated as the underlying factors of tissue selectivity of the SERMs. Nongenomic action, modulation of protein levels of ER and co-factors, and activation of other nuclear receptors, have been also reported as mechanisms of tissue selectivity by SERMs.

Animals↗