Ideal Selective Estrogen Receptor Modulators Research Articles

Searching for an ideal SERM: Mining tamoxifen structure–activity relationships

The repurposing of old drugs for new treatments has recently garnered increased attention in the face of new diseases and declining productivity of the pharmaceutial industry. This report draws attention to potential opportunities hiding in plain sight within the SAR of off-patent drugs. Herein we explore the untapped potential of Selective Estrogen Receptor Modulators (SERMs). SERMs are a class of molecules that have been highly influential in the treatment of estrogen receptor-positive breast cancers. However, the most commonly prescribed SERM, tamoxifen, has been found to increase the risk of endometrial cancer. Another SERM, raloxifene, does not increase incidence of endometrial cancer, but has been abandoned as a breast cancer treatment. We report the design, synthesis, and evaluation of an unexplored tamoxifen substitution pattern which mimics the geometry of raloxifene to confer its favorable pharmacodynamics. This substitution pattern was found to maintain excellent binding affinity to estrogen receptor-α.

Psoralen stimulates osteoblast proliferation through the activation of nuclear factor-κB-mitogen-activated protein kinase signaling.

Osteoporosis is a systemic skeletal disease that leads to increased bone fragility and susceptibility to fracture. Approximately 50% of postmenopausal women develop osteoporosis as a result of postmenopausal estrogen deficiency. To reduce fractures related to osteoporosis in women, previous studies have focused on therapeutic strategies that aim to increase bone formation or decrease bone resorption. However, pharmacological agents that aim to improve bone fracture susceptibility exhibit side effects. Current studies are investigating natural alternatives that possess the benefits of selective estrogen receptor modulators (SERMs) without the adverse effects. Recent studies have indicated that phytoestrogen may be an ideal natural SERM for the treatment of osteoporosis. In Chinese herbal medicine, psoralen, as the predominant substance of Psoralea corylifolia, is considered to be a phytoestrogen and is used as a remedy for osteoporosis. A number of studies have demonstrated the efficacy of psoralen in bone formation. However, the pathways and underlying molecular mechanisms that participate in psoralen-induced osteoblast formation are not well understood. In the present study, hFOB1.19 cells were treated with psoralen at different concentrations (0, 5, 10, 15 and 20 µM) for 0, 24, 36, 48 and 72 h, respectively. Reverse transcription-quantitative polymerase chain reaction and western blot assays were performed to detect glucose transporter 3 (GLUT3) expression. A cell counting kit-8 assay was used to analyze cell proliferation. In addition the effects of mitogen activated protein kinase inhibitors on extracellular signal-regulated kinase (ERK), phosphorylated (p)-ERK, p38, p-p38, c-Jun N-terminal kinase (JNK) and p-JNK expressions and cell proliferation were measured, as was the effect of nuclear factor (NF)-κB inhibitor on P65 and GLUT3 expressions and cell proliferation. The results indicated that psoralen stimulates hFOB1.19 cell proliferation in a dose-dependent manner (P<0.05). Phospho-ERK, p38 and JNK were markedly increased by psoralen compared with the control group (P<0.05), and the specific inhibitors of ERK (SCH772984), p38 (SB203580) and JNK (SP600125) reversed the stimulatory effects of psoralen on signal marker phosphorylation (P<0.05). The rate of psoralen-induced cell proliferation was significantly suppressed by inhibitors of ERK, JNK and p38 compared with psoralen treatment alone (P<0.05). In addition, psoralen stimulated osteoblast proliferation via the NF-κB signaling pathway. Therefore, the present findings suggest that psoralen may be a potential natural alternative to SERMs in the treatment of osteoporosis and fractures.

Anti-hormones: Mechanism and Use in Treatment of Breast Cancer

Breast cancer is the second-leading cause of cancer-related death in women. Recently, new drugs are being developed based on the molecular mechanisms of receptors, tumor suppressor genes, monoclonal antibodies, tumor markers and antihormone therapy. Anti-hormone therapy is used in the treatment of hormone-dependent breast tumors. Among the anti-hormone therapies, a substantial amount of research has been focused on the development of the ideal selective estrogen receptor modulator to treat metastatic breast tumors and to prevent breast cancer in high risk women.

Selective estrogen receptor modulators in the treatment of osteoporosis: a review of the clinical evidence

The ideal selective estrogen receptor modulator will protect against fractures, prevent estrogen receptor-positive breast cancer, suppress vasomotor symptoms, offer cardiovascular protection, maintain vaginal and bladder health and prevent endometrial stimulation, with an acceptable safety and tolerability profile. Raloxifene is available in most countries and has been approved for the prevention of vertebral (not nonvertebral fractures) and estrogen receptor-positive breast cancer but do not offer cardiovascular protection. The development of arzoxifene was terminated because superiority compared with raloxifene could not be shown. Bazedoxifene has a profile very similar to raloxifene, but protects against nonvertebral fracture in patients at high risk of fracture and has superior endometrial protection that allows pairing with conjugated estrogen. Bazedoxifene is approved and available in some countries. Lasofoxifene prevents vertebral and nonvertebral fractures and protects against cardiovascular event...

Lasofoxifene, from the preclinical drug discovery to the treatment of postmenopausal osteoporosis

Introduction: Estrogen replacement is traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women as well as for the management of menopausal symptoms. However, estrogen may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter is considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remains uncertain. Hence, there is a need for additional effective medications to prevent fractures in postmenopausal women that provide additional benefits.Areas covered: This article reviews lasofoxifene, a new SERM for the treatment of postmenopausal osteoporosis and urogenital atrophy. The medical literature is reviewed for articles containing the terms ‘lasofoxifene’ and ‘SERMs’. The manuscript reviews the discovery strategies and preclinical development of lasofoxifene as well as its clinical development.Expert opinion: Recent evidence suggests that the ideal SERM profile for one patient may be far from ideal for another. Thus, it could be favorable that different SERMs may be available in the future, each with a somewhat different profile that may be rationally applied to various patients with a spectrum of needs. In this context, lasofoxifene, while retaining some of the adverse effects of other SERMs (i.e., hot flushes and risk of venous thromboembolic events), may offer an improved skeletal efficacy over raloxifene, addressing other postmenopausal conditions, including reduction in breast cancer risk and treatment of vaginal atrophy.

SERMs and SERMs with estrogen for postmenopausal osteoporosis

Bone loss with aging places postmenopausal women at a higher risk for osteoporosis and its consequences such as fractures, pain, disability, and increased morbidity and mortality. Approximately 200 million patients worldwide are affected. The Third National Health and Nutrition Examination Survey (NHANES III) estimated that up to 18% of US women aged 50 and older have osteoporosis and up to 50% have osteopenia. Greater than 2 million osteoporotic related fractures occurred in the United States with direct healthcare costs exceeding $17 billion. Hormone Replacement Therapy (HRT) was a popular option for postmenopausal women before the Women's Health Initiative (WHI). Several agents are available in the U.S., including bisphosphonates, hormone therapy, calcitonin, parathyroid hormone and the selective estrogen receptor modulator (SERM) raloxifene. There are concerns about long term safety and compliance. Therefore, other agents are under investigation. SERMs are a diverse group of agents that bind to the estrogen receptor and each SERM appears to have a unique set of clinical responses, which are not always consistent with the typical responses seen with other SERMs. This article will discuss the SERMs approved in the United States, tamoxifene and raloxifene, and investigational SERMs. The ideal SERM would include the beneficial effects of estrogen in bone, heart and the central nervous system, with neutral or antagonistic effects in tissues where estrogen effects are undesirable(breast and endometrium). A new target in treating postmenopausal osteoporosis is the tissue estrogen complex or the pairing of a SERM with a conjugated estrogen known as a tissue selective estrogen complex (TSEC). This novel approach is currently being evaluated with bazodoxifene which could yield the beneficial effects of estrogens and SERMS, while potentially being more tolerable and safer than either therapy alone.

SERMs in the prevention and treatment of postmenopausal osteoporosis: an update

Selective estrogen receptor modulators (SERMs) have the ability to bind the estrogen receptor (ER) and are known to confer ER agonist or antagonist effects depending on the target tissue. A number of newer SERMs, including bazedoxifene, lasofoxifene and ospemifene, are currently under clinical development for the prevention and treatment of postmenopausal osteoporosis and for other indications. Although the possibility of developing a single agent that has all of the desired characteristics of an ideal SERM seems to be unlikely, progress in the clinical development of SERMs targeted to the ER suggests that these newer compounds may have attributes that represent an improvement relative to existing SERMs. A new approach to menopausal therapy is the tissue selective estrogen complex or the pairing of a selective estrogen receptor modulator with estrogens. Further investigation will help to clarify relative benefits/risks of novel SERMs in development within specific indications.

Another Selective Estrogen-Receptor Modulator for Osteoporosis

Selective estrogen-receptor modulators are nonsteroidal compounds that act as estrogen agonists in some tissues and as estrogen antagonists in others. Thus, they are uniquely suited for postmenopausal women. An ideal selective estrogen-receptor modulator would offer postmenopausal women the benefits of estrogen therapy (i.e., a reduced risk of fracture, urologic and vaginal atrophy, and hot flushes) without the risks (i.e., an increased risk of breast cancer, endometrial cancer, coronary heart disease, stroke, and venous thromboembolic events). Tamoxifen and raloxifene, the two selective estrogen-receptor modulators currently marketed for postmenopausal women in the United States, offer both benefits and drawbacks. Tamoxifen is associated . . .

Arzoxifene: the evidence for its development in the management of breast cancer

Endocrine therapy is an important and integral part of breast cancer management. Selective estrogen receptor modulators (SERMs), such as tamoxifen, remain a vital component in the endocrine therapy armamentarium. However the "ideal SERM", which has antagonist effects on the breast and endometrium but beneficial agonistic effects on bone and lipid profile, remains to be found. The aim of this review is to examine the evidence for arzoxifene as the "ideal SERM." Arzoxifene showed initial promise as the "ideal SERM" in preclinical, phase I, and phase II clinical studies. It appeared to have powerful antiestrogenic effects on breast cancer and endometrium, with equally strong favorable estrogenic effects on bone and lipid profile, minimal side effects, and good oral bioavailability. However, phase III trial data found it to be inferior to tamoxifen, bringing an apparent end to its investigation as a breast cancer treatment. Despite early promise as the "ideal SERM", results from a phase III trial have relegated arzoxifene to research in breast cancer prevention and osteoporosis treatment.

Arzoxifene: the development and clinical outcome of an ideal SERM

Hormone-sensitive tumours are among the most common cancers in women. Specific inhibition of the estrogen receptor by selective estrogen receptor downregulators or selective estrogen receptor modulators (SERMs) is effective for the treatment of breast and endometrial cancers and may be used for the prevention of breast cancer. Due to differential recruitment of co-activators and corepressors, SERMs are tissue specific and may have antiestrogenic effects in some tissues, with estrogen agonist activity in others. The ideal SERM would have antiestrogenic effects on the breast and endometrium, but pro-estrogenic effects on bone and lipids. The SERM, arzoxifene (LY-353381.HCl) meets all of these criteria. This review summarises the development, preclinical studies and the clinical outcome of arzoxifene and places it in context with other modalities in the treatment of hormone receptor-positive tumours.

Emerging Selective Estrogen Receptor Modulators

Menopause, regardless of age at onset, is associated with a marked increase in coronary heart disease (CHD) risk. On the basis of epidemiological studies that demonstrated mainly positive effects of postmenopausal hormone therapy on CHD as well as on risk markers of CHD, it has been suggested that CHD could be prevented in postmenopausal women with long-term hormone therapy. However, since the publications of the Heart and Estrogen/progestin Replacement Study and the Women's Health Initiative trial, prescription of hormone therapy for the prevention of CHD has become controversial. Major efforts have been made to identify alternatives for hormone therapy. Compounds suggested have included selective estrogen receptor modulators (SERMs), which represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This pharmacological profile may offer the opportunity to dissociate favourable estrogenic effects on the bone and cardiovascular system from unfavourable stimulatory effects on the breast and endometrium. Two SERMs presently on the market are tamoxifen and raloxifene. The only data available regarding the effects of tamoxifen on cardiovascular events in postmenopausal women are from breast cancer trials. These trials found fewer fatal myocardial events in women randomly assigned to tamoxifen compared with women assigned to placebo. Raloxifene is a second-generation SERM that has been shown to prevent osteoporotic fractures, is safe for the endometrium and holds high promise for the prevention of breast cancer. The effect of raloxifene on CHD is still uncertain. On the basis of the MORE (Multiple Outcomes of Raloxifene Evaluation) trial, raloxifene may offer some protection to women with CHD or to those who are at high risk of CHD. Proof that raloxifene reduces the risk of CHD requires a clinical trial with hard clinical endpoints. Such a study is currently underway. Next-generation SERMs taken into clinical development include idoxifene, droloxifene, ospemifene, arzoxifene, acolbifene/EM-800, levormeloxifene, lasofoxifene, bazedoxifene and HMR 3339. The aim is to find a compound with the ideal profile, that is, alleviation of climacteric symptoms and prevention of osteoporotic fractures, but without an adverse effect on the breast and endometrium, and no negative effect or even a beneficial effect on the cardiovascular system and the brain. Currently, limited data are available with regard to these next-generation SERMs and CHD. Nevertheless, some of these novel agents provide arguments for continuing the search for an ideal SERM.

436 PUBLICATION Results of cryosurgery in the treatment of patients with breast carcinoma

<dm:abstracts xmlns:dm="http://www.elsevier.com/xml/dm/dtd"><ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" view="all" class="author" id="aep-abstract-id1"><ce:section-title>Publisher Summary</ce:section-title><ce:abstract-sec view="all" id="aep-abstract-sec-id1"><ce:simple-para id="fsabs042" view="all">Selective estrogen receptor modulators (SERMs) constitute a group of chemical compounds that are distinct from estrogen. The ideal SERM would provide an estrogen-like effect at bone, preserving bone mass and reducing the risk of osteoporotic fracture. Additionally, it would lower the risk of coronary artery disease through improvements in lipoprotein profiles, improved vascular endothelial function, and possibly other mechanisms. Unlike estrogen, however, the ideal SERM would exert no proliferative effect at the uterine endometrium, so that there would be no regular or irregular uterine bleeding. This chapter discusses the current understanding of the mechanism of action of SERMs and reviews the effects on the skeleton of tamoxifen and raloxifene, the two SERMs for which there are both preclinical and clinical data. Additionaly, the clinical effects of these two drugs on lipids, uterus, and breast, as well as their overall clinical safety and tolerability, are considered.</ce:simple-para></ce:abstract-sec></ce:abstract></dm:abstracts>

Selective Estrogen-Receptor Modulators for Primary Prevention of Breast Cancer

Selective estrogen receptor modulators (SERMs) impact a variety of biologic processes regulated by activated estrogen receptor (ER). Depending on the target tissue, physiologic conditions, and their structure, SERMs may exhibit either estrogen antagonist or estrogen agonist effects. SERMs have a long history in the treatment of breast cancer, based on estrogen antagonist activity in ER-positive breast cancer cells. Beginning with tamoxifen, SERMs have moved to the prevention arena, where their partial estrogen effects may provide other organ benefits, particularly for postmenopausal women. It is because of these partial estrogen agonist effects on organs such as the bone, vagina, CNS, and cardiovascular system that SERMs are likely to remain preferable to pure antiestrogens as primary breast cancer prevention agents in the context of total women’s health. The ideal SERM should function as an antiestrogen in the breast and uterus and a partial estrogen agonist in skeletal, cardiovascular, CNS, gastrointestinal tract, and vagina. Further, this ideal SERM should be devoid of procoagulant effects and should not be associated with an increase in perimenopausal symptoms. Although several generations of SERMs have been developed, the ideal SERM for prevention remains elusive. We will review progress to date for SERMs as single agents and potential for combination therapy in the future. BIOLOGY BEHIND THE MULTIFACETED ACTION OF SERMs

Arzoxifene: a promising new selective estrogen receptor modulator for clinical chemoprevention of breast cancer.

Despite numerous major advances in the diagnostic, medical, and surgical management of breast cancer, the morbidity and mortality from this disease continue to be unacceptable. The need for a preventive approach to control breast cancer remains of paramount importance. Indeed, in the entire field of

A review of selective estrogen receptor modulators in the treatment of breast and endometrial cancer.

The understanding of how estrogen affects different body tissues by selective actions on the two subtypes of estrogen receptors (alpha and beta) has created the possibility of targeted therapy by the manufacturing of a group of compounds known as selective estrogen receptor modulators. The goal of an ideal selective estrogen receptor modulator that has all the beneficial effects of estrogen receptor modulation without adverse side effects seems increasingly achievable with improving drug design. The clinical findings for the new selective estrogen receptor modulator, arzoxifene, which has been shown to be highly active in the treatment of advanced breast cancer as well as advanced endometrial cancer, has confirmed the value of selective targeting of the estrogen receptors, and may herald a new era in endocrine therapy in clinical oncology.

A review of selective estrogen receptor modulators in the treatment of breast and endometrial cancer

The understanding of how estrogen affects different body tissues by selective actions on the two subtypes of estrogen receptors (alpha and beta) has created the possibility of targeted therapy by the manufacturing of a group of compounds known as selective estrogen receptor modulators. The goal of an ideal selective estrogen receptor modulator that has all the beneficial effects of estrogen receptor modulation without adverse side effects seems increasingly achievable with improving drug design. The clinical findings for the new selective estrogen receptor modulator, arzoxifene, which has been shown to be highly active in the treatment of advanced breast cancer as well as advanced endometrial cancer, has confirmed the value of selective targeting of the estrogen receptors, and may herald a new era in endocrine therapy in clinical oncology. Semin Oncol 29 (suppl 11):129-133. Copyright 2002, Elsevier Science (USA). All rights reserved.

Developing a SERM: stringent preclinical selection criteria leading to an acceptable candidate (WAY-140424) for clinical evaluation.

Estrogens are represented by a diverse group of compounds. Within this large family of molecules are tissue-selective estrogens that have been classified as selective estrogen receptor modulators (SERMs). These compounds are characterized by the fact that they exhibit both estrogen agonist and antagonist activity dependent upon the gene promoter and target tissue being examined. SERMs have been intensively studied over the past decade, especially since one, raloxifene, has been approved for the prevention and treatment of postmenopausal osteoporosis. While not a replacement for hormone replacement therapy (HRT), raloxifene can be an alternative to it and other treatments for osteoporosis. The ideal SERM would provide the positive benefits associated with HRT without the uterine and breast stimulation. Raloxifene does achieve some of the benefits of HRT, specifically on the skeleton and lipid metabolism with no apparent uterine effects, and a potential decreased risk of developing breast cancer associated with raloxifene therapy. However, there are a number of parameters that can be improved. A number of SERMs have been evaluated only to fail in development due to, for the most part, uterine safety issues. In order to develop an improved SERM, a stringent screening process was designed to select compounds that did not stimulate the uterus or breast. At the same time, these new compounds would have a positive impact on the skeleton and lipid metabolism with the additional improvement (over raloxifene) of a neutral effect on hot flashes. Under these strict conditions, WAY-140424 was developed and, to date, the preclinical pharmacology data have accurately predicted the clinical response demonstrated in phase I and II trials.

What would be the properties of an ideal SERM?

Selective estrogen receptor modulators (SERMs) are drugs that bind to the estrogen receptor (ER); in some tissues they act like estrogen (agonists), while in other tissues they oppose the action of estrogen (antagonists). The SERM tamoxifen acts as an estrogen antagonist in the breast in that it prevents and treats breast cancer, but it acts as an estrogen agonist in the endometrium, where it can induce cancer. Estrogen, and to a lesser extent SERMs, are effective in preventing and treating osteoporosis. Contrary to the prevalent hypothesis that estrogen provides benefit to women with regard to secondary prevention of coronary heart disease (CHD), randomized clinical trials have demonstrated that estrogen is associated with an increased risk of CHD in this population of women. Conflicting results have been reported on the effect of estrogens on cognitive function. The latest and largest randomized clinical trials have demonstrated a beneficial role in short-term memory in nondemented women, in contrast to the absence of such benefit in improving symptoms in women with Alzheimer's disease. Although estrogens have been used successfully to treat some menopausal symptoms such as hot flashes, the SERMs tamoxifen and raloxifene actually induce or increase hot flashes. Data on the beneficial and adverse effects of estrogen and SERMs are reported along with an elaboration of the constellation of properties that would characterize an ideal SERM working through the ER.

Selective Estrogen Receptor Modulation: The Search for an Ideal Hormonal Therapy for Breast Cancer

Female hormones, especially estrogens, play an important role in the pathogenesis of breast neoplasms and are a principal determinant of their biological behavior. Endocrine manipulation through medical or surgical means can often lead to objective shrinkage of breast tumors. Tamoxifen, a triphenylethylene estrogen receptor modulator, is currently the most widely used hormonal treatment for breast cancer. It has been conclusively demonstrated to reduce the risk of relapse following definitive local therapy (and systemic chemotherapy, when indicated) of invasive or noninvasive breast cancer. Recently, it has also been shown to reduce the incidence of breast cancer in healthy women who are at high risk of developing the disease. In addition, it can prevent osteoporosis and reduce the risk of fractures in postmenopausal women. However, its use is also complicated by an increased incidence of endometrial hyperplasia/carcinoma, venous thromboembolism, cataracts, and in some cases, emergence of tamoxifen-dependent clones of breast cancer. These side effects (except cataracts) are believed to be related to estrogen-agonist effects of tamoxifen. Newer drugs, which are “pure antiestrogens” or inhibitors of estrogen biosynthesis, are devoid of such estrogen-agonist activity and may not have the liability of many of these side effects. However, these agents would also be expected to lack the potentially beneficial effects of tamoxifen on lipids and skeletal system. The ability of tamoxifen to act as an estrogen-agonist or estrogen-antagonist in a tissue-specific fashion has led to the concept of selective estrogen-receptor modulation. Selective estrogen receptor modulators (SERMs), which are devoid of estrogenagonist effects on the uterus or breast cancer cells but retain potentially beneficial effects on bones and lipids, have been described as “ideal” SERMs. A number of such compounds are currently being tested. Raloxifene is already approved for prevention of osteoporosis and has potential efficacy for prevention and treatment of breast cancer. An analogue of raloxifene, LY353381, is currently in Phase II clinical trials for treatment of breast cancer, with promising early results. EM800 and CP336156 are other promising ideal SERMs in clinical trials. These compounds may provide better treatment and chemoprevention alternatives for breast cancer as compared to tamoxifen, aromatase inhibitors, and pure antiestrogens. In addition, they may also prove to be useful for the treatment and prevention of prostate cancer as well as for treating benign gynecological diseases such as fibroids and endometriosis. Future laboratory efforts should focus on further broadening the efficacy profile of SERMs (e.g., prevention of Alzheimer's disease and elevation of high-density lipoproteins to improve the likelihood of cardiovascular benefit) and narrowing their side-effect profile (e.g., risk of thromboembolism and hot flashes).