View source for Selective estrogen receptor modulator

{{Short description|Drugs acting on the estrogen receptor}}
{{Infobox drug class
| Image = Tamoxifen2DACS.svg
| ImageClass = skin-invert-image
| Alt =
| Caption = [[Tamoxifen]], a [[nonsteroidal]] [[triphenylethylene]] antiestrogen and a widely used drug in the treatment of [[breast cancer]].
| Width = 250px
| Synonyms = SERM; Estrogen receptor agonist/antagonist; ERAA
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| Use = [[Breast cancer]], [[infertility]], [[osteoporosis]], [[vaginal atrophy]], [[dyspareunia]], [[hormonal contraceptive|contraception]], [[male hypogonadism]], [[gynecomastia]], [[breast pain]], others
| ATC_prefix = G03XC
| Biological_target = [[Estrogen receptor]]
| Chemical_class =
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| Consumer_Reports =
| medicinenet =
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'''Selective estrogen receptor modulators''' ('''SERMs'''), also known as '''estrogen receptor agonists/antagonists''' ('''ERAAs'''),<ref name="pmid28628428">{{cite journal | vauthors = Hirsch HD, Shih E, Thacker HL | title = ERAAs for menopause treatment: Welcome the 'designer estrogens' | journal = Cleve Clin J Med | volume = 84 | issue = 6 | pages = 463–470 | date = June 2017 | pmid = 28628428 | doi = 10.3949/ccjm.84a.15140 | doi-access = free }}</ref><ref name="pmid32576803">{{cite journal | vauthors = Archer DF | title = Ospemifene: less venous thrombosis than other selective estrogen receptor modulators in postmenopausal women with vulvo vaginal atrophy | journal = Menopause | volume = 27 | issue = 8 | pages = 846–847 | date = August 2020 | pmid = 32576803 | doi = 10.1097/GME.0000000000001600 | s2cid = 220045301 }}</ref> are a class of [[drug]]s that act on [[estrogen receptor]]s (ERs).<ref name="Riggs_2003">{{cite journal | vauthors = Riggs BL, Hartmann LC | title = Selective estrogen-receptor modulators -- mechanisms of action and application to clinical practice | journal = The New England Journal of Medicine | volume = 348 | issue = 7 | pages = 618–29 | date = Feb 2003 | pmid = 12584371 | doi = 10.1056/NEJMra022219 }}</ref> Compared to pure ER [[agonist]]s–[[Receptor antagonist|antagonists]] (e.g., [[full agonist]]s and [[silent antagonist]]s), SERMs are more tissue-specific, allowing them to selectively inhibit or stimulate [[estrogen]]-like action in various tissues.

{{TOC limit|3}}

== Medical uses ==
SERMs are used for various estrogen-related diseases, including treatment of [[Ovulatory dysfunction|ovulatory]] dysfunction in the management of [[infertility]] treatment, prevention of [[Osteoporosis|postmenopausal osteoporosis]], treatment and risk reduction of [[breast cancer]],<ref name="Maximov_2013">{{cite journal |vauthors = Maximov PY, Lee TM, Jordan VC|title = The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice|journal = Current Clinical Pharmacology|volume = 8|issue = 2|pages = 135–55|date = May 2013|pmid = 23062036|pmc = 3624793|doi = 10.2174/1574884711308020006}}</ref> and treatment of [[dyspareunia]] due to [[menopause]]. SERMs are also used in combination with [[conjugated estrogens]] indicated for the management of [[Hypoestrogenism|estrogen deficiency]] symptoms and of [[vasomotor]] symptoms associated with menopause.<ref name="Pickar_2015" />

SERMs are also being explored for [[gender-affirming hormone therapy]] in some [[Non-binary gender|non-binary]] transgender individuals that were assigned male at birth. Unlike full estrogen receptor agonists like [[Estradiol (medication)|estradiol]] which cause the broad development of feminine [[Secondary sex characteristic|secondary sex characteristics]], SERMs can be used to achieve partial feminization in individuals who wish to develop certain feminine traits such as softer skin and feminine body fat distribution without significant breast growth.<ref>{{Cite journal |last1=Xu |first1=Jane Y. |last2=O’Connell |first2=Michele A. |last3=Notini |first3=Lauren |last4=Cheung |first4=Ada S. |last5=Zwickl |first5=Sav |last6=Pang |first6=Ken C. |date=2021-06-18 |title=Selective Estrogen Receptor Modulators: A Potential Option For Non-Binary Gender-Affirming Hormonal Care? |journal=Frontiers in Endocrinology |language=en |volume=12 |doi=10.3389/fendo.2021.701364 |doi-access=free |pmid=34226826 |pmc=8253879 |issn=1664-2392 }}</ref> Unlike bioidentical estrogens, SERMs themselves do not suppress testosterone production and therefore are used alongside [[Antiandrogen|antiandrogens]] such as [[cyproterone acetate]] or [[spironolactone]]. The use of SERMs for gender-affirming hormone therapy is still relatively new and uncommon as there is limited research into their efficacy and safety when used long-term. <ref>{{Cite journal |last=Hodax |first=Juanita K. |last2=DiVall |first2=Sara |date=2023-01-01 |title=Gender-affirming endocrine care for youth with a nonbinary gender identity |url=https://journals.sagepub.com/doi/full/10.1177/20420188231160405 |journal=Therapeutic Advances in Endocrinology and Metabolism |language=en |volume=14 |pages=20420188231160405 |doi=10.1177/20420188231160405 |issn=2042-0188 |pmc=10064168 |pmid=37006780}}</ref>

[[File:Nolvadex.jpg| thumb| Nolvadex ([[tamoxifen]]) 20-milligram tablets ([[United Kingdom|UK]])]]

==Examples==

[[Tamoxifen]] is a first-line [[Hormone therapy|hormonal treatment]] for ER-positive metastatic [[breast cancer]]. It is used for breast cancer risk reduction in women at high risk, and as [[Adjuvant therapy|adjuvant treatment]] for [[axillary node]]-negative and node-positive [[ductal carcinoma]] ''[[in situ]]''.<ref name="Pickar_2015" /><ref name="Mirkin_2015" /> Tamoxifen treatment is also used for the treatment of [[osteoporosis]] and [[blood lipids]] in postmenopausal women. Adverse effects of tamoxifen include [[hot flash]]es and an increase in the risk of developing [[endometrial cancer]] compared to women of similar age.<ref name="Mirkin_2015" /><ref name="Maximov_2013" />

[[Toremifene]], a [[chlorinated]] tamoxifen derivative developed to avoid [[Hepatocellular carcinoma|hepatic carcinomas]], was associated with fewer [[DNA adducts]] in the liver than tamoxifen in [[preclinical studies]]. It is used as [[Endocrine system|endocrine]] therapy for women with estrogen or [[progesterone receptor]]-positive, stage 4 or recurrent metastatic breast cancer<ref name="Miller_2002" /> and has demonstrated similar efficacy compared to tamoxifen as adjuvant treatment of breast cancer and in the treatment of metastatic breast cancer.<ref name="Mirkin_2015" />

[[Raloxifene]] is used for the prevention and treatment of [[Menopause|postmenopausal]] osteoporosis and breast cancer prevention in high-risk postmenopausal women with osteoporosis.<ref name=Pickar_2015 /> Preclinical and clinical reports suggest that it is considerably less potent than estrogen for the treatment of osteoporosis. It is associated with an acceptable endometrial profile and has not demonstrated tamoxifen-like effects on the uterus, but has been associated with adverse effects such as [[venous thromboembolism]] and vasomotor symptoms, including hot flushes.<ref name="Maximov_2013"/>

[[Ospemifene]] is an analogous [[metabolite]] of toremifene. Unlike tamoxifen, toremifene is not a rat [[hepatocarcinogen]], and therefore ospemifene would also be a safer SERM than tamoxifen.<ref name="Maximov_2013"/> It is used for the treatment of moderate to severe dyspareunia, a symptom of [[vulva]]r and [[Atrophic vaginitis|vaginal atrophy]] associated with menopause. Clinical data on breast cancer are not available, but both ''in vitro'' and ''in vivo'' data suggest that ospemifene may have [[chemopreventive]] activity in breast tissue.<ref name="Mirkin_2015" />

[[Bazedoxifene]] is used for treatment of osteoporosis in postmenopausal women at increased risk of [[Bone fracture|fracture]]. It has been shown to be relatively safe and well-tolerated. It shows no breast or endometrial stimulation and in the first two years the small increase is better in venous thromboembolism, and similar in the long term to other SERMs. The advantage of bazedoxifene over raloxifene is that it increases [[endothelial nitric oxide synthase]] activity and does not antagonize the effect of [[17β-estradiol]] on vasomotor symptoms.<ref name=Pickar_2015 />

The first [[tissue-selective estrogen complex]] (TSEC) combines [[conjugated estrogens]] and the SERM bazedoxifene to blend their activities. The combination therapy is used in the treatment of moderate to severe vasomotor symptoms associated with menopause, prevention of postmenopausal osteoporosis as well as treatment of [[Hypoestrogenism|estrogen deficiency]] symptoms in non-[[Hysterectomy|hysterectomized]] postmenopausal women. The combination allows for the benefits of estrogen with regard to relief of vasomotor symptoms without estrogenic stimulation of the [[endometrium]].<ref name=Pickar_2015 /><ref name="Mirkin_2015" />

SERMs have also been used in [[hormone replacement therapy]] by some [[transgender]] people.<ref>{{cite journal |last1=Xu |first1=Jane Y. |last2=O'Connell |first2=Michele A. |last3=Notini |first3=Lauren |last4=Cheung |first4=Ada S. |author4-link=Ada Cheung |last5=Zwickl |first5=Sav |last6=Pang |first6=Ken C. |title=Selective Estrogen Receptor Modulators: A Potential Option For Non-Binary Gender-Affirming Hormonal Care? |journal=Frontiers in Endocrinology |date=18 June 2021 |volume=12 |pages=701364 |doi=10.3389/fendo.2021.701364 |pmid=34226826 |pmc=8253879 |issn=1664-2392 |doi-access=free }}</ref>

[[10β,17β-Dihydroxyestra-1,4-dien-3-one|DHED]] is a '''centrally selective''', orally active prodrug of estradiol. 

=== Available forms ===
{| class="wikitable sortable mw-collapsible <!--mw-collapsed-->" style="margin-left: auto; margin-right: auto; border: none;"
|+ class="nowrap" | SERMs marketed for clinical or veterinary use
|-
! Name !! Brand&nbsp;name !! Approved uses !! Launch !! Notes
|-
| [[Anordrin]] || Zi Yun || [[Emergency contraception]] || 1970s || Only in [[China]], combined with [[mifepristone]]
|-
| [[Bazedoxifene]] || Duavee || [[Osteoporosis]] prevention || 2013 || Combined with [[conjugated estrogens]]
|-
| [[Broparestrol]] || Acnestrol || [[Dermatology]]; [[Breast cancer]] treatment || 1970s || Discontinued
|-
| [[Clomifene]] || Clomid || [[Female infertility]] || 1967 ||
|-
| [[Cyclofenil]] || Sexovid || Female infertility; [[Menopausal symptoms]] || 1970 || Mostly discontinued
|-
| [[Lasofoxifene]] || Fablyn || Osteoporosis prevention, treatment; [[Vaginal atrophy]] || 2009 || Only in [[Lithuania]] and [[Portugal]]
|-
| [[Ormeloxifene]] || Saheli || [[Hormonal contraception]] || 1991 || Only in [[India]]
|-
| [[Ospemifene]] || Osphena || [[Dyspareunia]] due to vaginal atrophy || 2013 ||
|-
| [[Raloxifene]] || Evista || Osteoporosis prevention, treatment; Breast cancer prevention || 1997 ||
|-
| [[Tamoxifen]] || Nolvadex || Breast cancer treatment || 1978 ||
|-
| [[Toremifene]] || Fareston || Breast cancer treatment || 1997 ||
|- class="sortbottom"
| colspan="5" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Sources:''' See individual articles.
|}

== Pharmacology ==

=== Pharmacodynamics ===

SERMs are competitive partial agonists of the ER.<ref name="CameronCameron2013">{{cite book | first1 = John L. | last1 = Cameron | first2 = Andrew M | last2 = Cameron | name-list-style = vanc | title = Current Surgical Therapy | url = https://books.google.com/books?id=QwYyAgAAQBAJ&pg=PA582|date=20 November 2013|publisher=Elsevier Health Sciences|isbn=978-0-323-22511-3|pages=582–}}</ref> Different tissues have different degrees of sensitivity to the activity of endogenous estrogens, so SERMs produce estrogenic or [[antiestrogen]]ic effects depending on the tissue in question, as well as the percentage of [[intrinsic activity]] (IA) of the SERM.<ref name="Huang_Aslanian_2012">{{cite book | first1 = Xianhai | last1 = Huang | first2 = Robert G. | last2 = Aslanian | name-list-style = vanc | title = Case Studies in Modern Drug Discovery and Development|url=https://books.google.com/books?id=MvsSTJigQcMC&pg=PA392|date=19 April 2012|publisher=John Wiley & Sons|isbn=978-1-118-21967-6|pages=392–394}}</ref> An example of a SERM with high IA and thus mostly estrogenic effects is [[chlorotrianisene]], while an example of a SERM with low IA and thus mostly antiestrogenic effects is [[ethamoxytriphetol]]. SERMs like [[clomifene]] and [[tamoxifen]] are comparatively more in the middle in their IA and their balance of estrogenic and antiestrogenic activity. [[Raloxifene]] is a SERM that is more antiestrogenic than tamoxifen; both are estrogenic in bone, but raloxifene is antiestrogenic in the [[uterus]] while tamoxifen is estrogenic in this part of the body.<ref name="Huang_Aslanian_2012" />

{{Tissue-specific estrogenic and antiestrogenic activity of SERMs}}

{{Affinities of estrogen receptor ligands for the ERα and ERβ}}

==== Binding site ====
{{See also|Estrogen receptor}}
[[Image:Er domains.svg| thumb| 400px|class=skin-invert-image|The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.]]

SERM act on the estrogen receptor (ER), which is an [[intracellular]], ligand-dependent [[transcriptional activator]] and belongs to the [[nuclear receptor]] family.<ref name="Kremoser_2007">{{cite journal | vauthors = Kremoser C, Albers M, Burris TP, Deuschle U, Koegl M | title = Panning for SNuRMs: using cofactor profiling for the rational discovery of selective nuclear receptor modulators | journal = Drug Discovery Today | volume = 12 | issue = 19–20 | pages = 860–9 | date = Oct 2007 | pmid = 17933688 | doi = 10.1016/j.drudis.2007.07.025 }}</ref> Two different subtypes of ER have been identified, [[Estrogen receptor alpha|ERα]] and [[Estrogen receptor beta|ERβ]]. ERα is considered the main medium where estrogen signals are [[Transduction (genetics)|transduced]] at the transcriptional level and is the predominant ER in the female reproductive tract and mammary glands while ERβ is primarily in vascular [[endothelial cells]], bone, and male prostate tissue.<ref name="Rosano_2011"/> ERα and ERβ concentration are known to be different in tissues during development, aging or disease state.<ref name="Nilsson_2011">{{cite journal | vauthors = Nilsson S, Koehler KF, Gustafsson JÅ | title = Development of subtype-selective oestrogen receptor-based therapeutics | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 10 | pages = 778–92 | date = Oct 2011 | pmid = 21921919 | doi = 10.1038/nrd3551 | s2cid = 23043739 }}</ref> Many characteristics are similar between these two types such as size (~600 and 530 [[amino acid]]s) and structure. ERα and ERβ share approximately 97% of the amino-acid sequence identity in the [[DNA-binding domain]] and about 56% in the [[ligand-binding domain]].<ref name="Kremoser_2007" /><ref name="Nilsson_2011" /> The main difference of the ligand-binding domains is determined by [[Leucine|Leu]]-384 and [[Methionine|Met]]-421 in ERα, which are replaced by Met-336 and [[Isoleucine|Ile]]-373, respectively, in ERβ.<ref name="Koehler_2005">{{cite journal | vauthors = Koehler KF, Helguero LA, Haldosén LA, Warner M, Gustafsson JA | title = Reflections on the discovery and significance of estrogen receptor beta | journal = Endocrine Reviews | volume = 26 | issue = 3 | pages = 465–78 | date = May 2005 | pmid = 15857973 | doi = 10.1210/er.2004-0027 | doi-access = free }}</ref> The variation is greater on the N-terminus between ERα and ERβ.<ref name="Duterte_2000">{{cite journal | vauthors = Dutertre M, Smith CL | title = Molecular mechanisms of selective estrogen receptor modulator (SERM) action | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 295 | issue = 2 | pages = 431–7 | date = Nov 2000 | doi = 10.1016/S0022-3565(24)38923-2 | pmid = 11046073 | url = http://jpet.aspetjournals.org/content/295/2/431.short | url-access = subscription }}</ref>

DNA-binding domain consists of two subdomains. One with a proximal box that is involved in DNA recognition while the other contains a distal box responsible for DNA-dependent, DNA-binding domain [[Dimer (chemistry)|dimerization]]. The proximal box sequence is identical between ERα and ERβ, which indicates similar specificity and affinity between the two subgroups. DNA-binding domain's globular proteins contain eight [[cysteine]]s and allow for a tetrahedral coordination of two [[zinc]] ions. This coordination makes the binding of ER to estrogen response elements possible.<ref name="Rosano_2011" /> The ligand-binding domain is a globular, three-layered structure made of 11 [[helix]]es and contains a pocket for the natural or synthetic ligand.<ref name="Rosano_2011" /><ref name="Kremoser_2007" /> Influencing factors for binding affinity are mainly the presence of a [[phenol]] moiety, molecular size and shape, double bonds and [[hydrophobicity]].<ref name="Xu_2010">{{cite journal | vauthors = Xu X, Yang W, Li Y, Wang Y | title = Discovery of estrogen receptor modulators: a review of virtual screening and SAR efforts | journal = Expert Opinion on Drug Discovery | volume = 5 | issue = 1 | pages = 21–31 | date = Jan 2010 | pmid = 22823969 | doi = 10.1517/17460440903490395 | s2cid = 207492889 }}</ref>

The differential positioning of the activating function 2 (AF-2) helix 12 in the ligand-binding domain by the bound ligand determines whether the ligand has an agonistic and antagonistic effect. In agonist-bound receptors, helix 12 is positioned adjacent to helices 3 and 5. Helices 3, 5, and 12 together form a binding surface for an NR box motif contained in [[Coactivator (genetics)|coactivators]] with the [[Consensus sequence|canonical sequence]] LXXLL (where L represents [[leucine]] or [[isoleucine]] and X is any amino acid). Unliganded (apo) receptors or receptors bound to antagonist ligands turn helix 12 away from the LXXLL-binding surface that leads to preferential binding of a longer leucine-rich motif, LXXXIXXX(I/L), present on the [[corepressor]]s NCoR1 or SMRT. In addition, some [[Cofactors and coenzymes|cofactors]] bind to ER through the terminals, the DNA-binding site or other binding sites. Thus, one compound can be an ER agonist in a tissue rich in [[Coactivator (genetics)|coactivators]] but an ER antagonist in tissues rich in [[Co-repressor|corepressors]].<ref name="Kremoser_2007" />

=== Mechanism of action ===
[[Image:NR mechanism.png| thumb| 480px| Structural basis for the mechanism of estrogen receptor agonist and antagonist action.<ref name = "Brzozowski_1997">{{cite journal | vauthors = Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O, Öhman L, Greene GL, Gustafsson JÅ, Carlquist M | title = Molecular basis of agonism and antagonism in the oestrogen receptor | journal = Nature | volume = 389 | issue = 6652 | pages = 753–8 | year = 1997 | doi = 10.1038/39645 | pmid = 9338790 | bibcode = 1997Natur.389..753B | s2cid = 4430999 }}</ref> The structures shown here are of the ligand binding domain (LBD) of the estrogen receptor (green cartoon diagram) complexed with either the agonist [[diethylstilbestrol]] (top, {{PDB|3ERD}}) or antagonist [[4-hydroxytamoxifen]] (bottom, {{PDB2|3ERT}}). The ligands are depicted as space filling spheres (white = carbon, red = oxygen). When an agonist is bound to a nuclear receptor, the C-terminal [[alpha helix]] of the LBD (H12; light blue) is positioned such that a [[coactivator (genetics)|coactivator]] protein (red) can bind to the surface of the LBD. Shown here is just a small part of the coactivator protein, the so-called NR box containing the LXXLL amino acid sequence motif.<ref name = "Shiau_1998">{{cite journal | vauthors = Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL | title = The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen | journal = Cell | volume = 95 | issue = 7 | pages = 927–37 | year = 1998 | doi = 10.1016/S0092-8674(00)81717-1 | pmid = 9875847 | s2cid = 10265320 | doi-access = free }}</ref> Antagonists occupy the same ligand binding cavity of the nuclear receptor. However antagonist ligands in addition have a sidechain extension which [[steric effects|sterically]] displaces H12 to occupy roughly the same position in space as coactivators bind. Hence coactivator binding to the LBD is blocked.]]

Estrogenic compounds span a spectrum of activity, including:{{cn|date=January 2025}}
* Full agonists (agonistic in all tissues), such as the natural endogenous hormone [[estradiol]].
* Mixed agonists/antagonistic (agonistic in some tissues while antagonistic in others), such as tamoxifen (a SERM).
* Pure antagonists (antagonistic in all tissues), such as [[fulvestrant]].

SERMs are known to stimulate estrogenic actions in tissues such as the liver, bone and cardiovascular system but known to block estrogen action where stimulation is not desirable, such as in the breast and the uterus.<ref name="Musa_2007"/> This agonistic or antagonistic activity causes varied structural changes of the receptors, which results in activation or repression of the estrogen target genes.<ref name="Riggs_2003"/><ref name="Musa_2007" /><ref name="Maximov_2013"/><ref name="Lewis_2005">{{cite journal | vauthors = Lewis JS, Jordan VC | title = Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance | journal = Mutation Research | volume = 591 | issue = 1–2 | pages = 247–63 | date = Dec 2005 | pmid = 16083919 | doi = 10.1016/j.mrfmmm.2005.02.028 | bibcode = 2005MRFMM.591..247L }}</ref> SERMs interact with receptors by diffusing into cells and their binding to ERα or ERβ subunits, which results in [[Protein dimer|dimerization]] and structural changes of the receptors. This makes it easier for the SERMs to interact with estrogen response elements which leads to the activation of estrogen-inducible genes and mediating the estrogen effects.<ref name="Musa_2007" />

SERMs unique feature is their tissue- and cell-selective activity. There is growing evidence to support that SERM activity is mainly determined by selective recruitment of corepressors and coactivators to ER target genes in specific types of tissues and cells.<ref name="Maximov_2013" /><ref name="Lewis_2005" /><ref name="Feng_2014">{{cite journal | vauthors = Feng Q, O'Malley BW | title = Nuclear receptor modulation--role of coregulators in selective estrogen receptor modulator (SERM) actions | journal = Steroids | volume = 90 | pages = 39–43 | date = Nov 2014 | pmid = 24945111 | doi = 10.1016/j.steroids.2014.06.008 | pmc=4192004}}</ref> SERMs can impact coactivator protein stability and can also regulate coactivator activity through [[post-translational modification]]s such as [[phosphorylation]]. Multiple growth signaling pathways, such as [[HER2]], [[Protein kinase C|PKC]], [[PI3K]] and more, are [[Downregulation|downregulated]] in response to anti-estrogen treatment. Steroid receptor coactivator 3 (SRC-3) is phosphorylated by activated [[kinase]]s that also enhance its coactivator activity, affect cell growth and ultimately contribute to drug resistance.<ref name="Feng_2014" />

The ratio of ERα and ERβ at a target site may be another way SERM activity is determined. High levels of cellular proliferation correlate well with a high ERα:ERβ ratio, but repression of cellular proliferation correlates to ERβ being dominant over ERα. The ratio of ERs in [[Neoplasm|neoplastic]] and normal breast tissue could be important when considering [[chemoprevention]] with SERMs.<ref name="Riggs_2003" /><ref name="Musa_2007" /><ref name="Maximov_2013" /><ref name="Lewis_2005" />

When looking at the differences between ERα and ERβ, Activating Function 1 (AF-1) and AF-2 are important. Together they play an important part in the interaction with other co-regulatory proteins that control [[gene transcription]].<ref name="Musa_2007" /><ref name="Maximov_2013" /> AF-1 is located in the [[amino terminus]] of the ER and is only 20% homologous in ERα and ERβ. On the other hand, AF-2 is very similar in ERα and ERβ, and only one amino acid is different.<ref name="Maximov_2013" /> Studies have shown that by switching AF-1 regions in ERα and ERβ, that there are specific differences in transcription activity. Generally, SERMs can partially activate engineered genes through ERα by an estrogen receptor element, but not through ERβ.<ref name="Musa_2007" /><ref name="Maximov_2013" /><ref name="Lewis_2005" /> Although, raloxifene and the active form of tamoxifen can stimulate AF-1-regulated reporter genes in both ERα and ERβ.<ref name="Maximov_2013" />

Because of the discovery that there are two ER subtypes, it has brought about the synthesis of a range of receptor specific ligands that can switch on or off a particular receptor.<ref name="Maximov_2013" /> However, the external shape of the resulting complex is what becomes the catalyst for changing the response at a tissue target to a SERM.<ref name="Riggs_2003" /><ref name="Musa_2007" /><ref name="Maximov_2013" /><ref name="Lewis_2005" />

[[X-ray crystallography]] of estrogens or antiestrogens has shown how ligands program the receptor complex to interact with other proteins. The ligand-binding domain of the ER demonstrates how ligands promote and prevent coactivator binding based on the shape of the estrogen or antiestrogen complex. The broad range of ligands that bind to the ER can create a spectrum of ER complexes that are fully estrogenic or antiestrogenic at a specific target site.<ref name="Riggs_2003" /><ref name="Maximov_2013" /><ref name="Lewis_2005" /> The main result of a ligand-binding to ER is a structural rearrangement of the ligand-[[Active site|binding pocket]], primarily in the AF-2 of the C-terminal region. The binding of ligands to ER leads to the formation of a [[hydrophobic]] pocket that regulates cofactors and receptor pharmacology. The correct [[Protein folding|folding]] of ligand-binding domain is required for activation of transcription and for ER to interact with a number of coactivators.<ref name="Maximov_2013" />

Coactivators are not just protein partners that connect sites together in a complex. Coactivators play an active role in modifying the activity of a complex. Post-translation modification of coactivators can result in a dynamic model of [[steroid hormone]] action by way of multiple kinase pathways initiated by cell surface [[growth factor receptor]]s. Under the guidance of a multitude of protein remodelers to form a multiprotein coactivator complex that can interact with the phosphorylated ER at a specific gene promoter site, the core coactivator first has to recruit a specific set of cocoactivators. The proteins that the core coactivator assembles as the core coactivated complex have individual enzymatic activities to [[Methylation|methylate]] or [[Acetylation|acetylate]] adjacent proteins. The ER substrates or [[coenzyme A]] can be [[Polyubiquitination|polyubiquitinated]] by multiple cycles of the reaction or, depending on linkage proteins, they can either be activated further or degraded by the [[26S proteasome]].<ref name="Maximov_2013" />

Consequently, to have an effective gene transcription that is programmed and targeted by the structure and phosphorylation status of the ER and coactivators, it is required to have a dynamic and cyclic process of remodeling capacity for transcriptional assembly, after which the transcription complex is then instantly routinely destroyed by the proteasome.<ref name="Maximov_2013" />

== Structure and function ==

=== Structure–activity relationships ===
The core structure of SERMs simulates the [[17β-estradiol]] template. They have two [[aromatic rings]] separated by 1-3 atoms (often a [[stilbene]]-type of arrangement). Between the two [[phenyl]]s of the core, SERMs typically have a 4-substituted phenyl group that, when bound to ER, projects from a position of an [[estratriene]] nucleus so that helix 12 moves from the receptor opening and blocks the space where coactivator proteins would normally bind and cause ER agonist activity. There has been a lot of variations in the core portion of SERMs while there has been less flexibility with what is tolerated in the [[side chain]].<ref name="Miller_2002" /> SERMs can be classified by their core structure.

==== First-generation triphenylethylenes ====
[[File:4OHT vs E2 2.png|thumb|150px|class=skin-invert-image|4-Hydroxytamoxifen (red) overlaid with 17β-estradiol (black)]]
The first main structural class of SERM-type molecules reported are the [[triphenylethylene]]s. The stilbene core (similar to the nonsteroidal estrogen, diethylstilbestrol) essentially mimics steroidal estrogens such as 17β-estradiol, while the side chain overlays with the 11th position of the steroid nucleus.<ref name="Miller_2002" /> Triphenylethylene derivatives have an additional phenyl group attached to the [[ethylene]] bridge group. The 3-position [[H-bonding]] ability of phenols is a significant requirement for ER binding.<ref name="Fang_2001">{{cite journal | vauthors = Fang H, Tong W, Shi LM, Blair R, Perkins R, Branham W, Hass BS, Xie Q, Dial SL, Moland CL, Sheehan DM | title = Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens | journal = Chemical Research in Toxicology | volume = 14 | issue = 3 | pages = 280–94 | date = Mar 2001 | pmid = 11258977 | doi = 10.1021/tx000208y | citeseerx = 10.1.1.460.20 }}</ref>
[[File:Clomifene2.png|thumb|150px|left|class=skin-invert-image|''trans''-Form of clomifene with the triphenylethylene structure in red.]]

The first drug, clomifene,<ref name="Clark_1981">{{cite journal | vauthors = Clark JH, Markaverich BM | title = The agonistic-antagonistic properties of clomiphene: a review | journal = Pharmacology & Therapeutics | volume = 15 | issue = 3 | pages = 467–519 | pmid = 7048350 | doi = 10.1016/0163-7258(81)90055-3 | year=1981}}</ref> has a chloro-[[substituent]] on the ethylene side chain which produces similar binding affinities as the later discovered drug tamoxifen. Clomifene is a mixture of estrogenic ([[Cis-trans isomerism|cis-form]]) and antiestrogenic [[isomer]]s ([[Cis-trans isomerism|trans-form]]).<ref name="Fang_2001" /> Cis and trans are defined in terms of the geometric relationships of the two unsubstituted phenyl rings.<ref name=Clark_1981 /> The two isomers of clomifene have different profiles, where the trans-form has activity more similar to tamoxifen while the cis-form behaves more like 17β-estradiol.<ref name="Miller_2002" /> Cis is approximately ten times more potent than trans. However, trans isomer is the most potent stimulator of epithelial cell hypertrophy since clomifene is antagonistic at low doses and agonistic at high doses.<ref name="Clark_1981" /> The antagonist isomers may cause inhibitory estrogenic effects in the uterus and mammary cancers, but the estrogenic isomer could combine with novel receptors to produce estrogen-like effects in bone.<ref name="Jensen_2003">{{cite journal | vauthors = Jensen EV, Jordan VC | title = The estrogen receptor: a model for molecular medicine | journal = Clinical Cancer Research | volume = 9 | issue = 6 | pages = 1980–9 | date = Jun 2003 | pmid = 12796359 }}</ref>

[[File:Tamoxifen2DACS.svg|thumb|150px|class=skin-invert-image|Chemical structure of tamoxifen]]

Tamoxifen has become the treatment of choice for women diagnosed with all stages of hormone-responsive breast cancer, that is, breast cancer that is both ER and/or progesterone positive. In the US, it is also administered for prophylactic chemoprevention in women identified as high risk for breast cancer.<ref>{{cite journal | vauthors = Singh MN, Stringfellow HF, Paraskevaidis E, Martin-Hirsch PL, Martin FL | title = Tamoxifen: important considerations of a multi-functional compound with organ-specific properties | journal = Cancer Treatment Reviews | volume = 33 | issue = 2 | pages = 91–100 | date = Apr 2007 | pmid = 17178195 | doi = 10.1016/j.ctrv.2006.09.008 }}]</ref> Tamoxifen is a pure antiestrogenic trans-isomer and has differential actions at estrogen target tissues throughout the body. Tamoxifen is selectively antiestrogenic in the breast but estrogen-like in bones and endometrial cancer.<ref name="Jensen_2003" /> Tamoxifen undergo phase I metabolism in the liver by microsomal [[Cytochrome P450|cytochrome P450 (CYP) enzymes]]. The major metabolites of tamoxifen are ''N''-desmethyltamoxifen and [[Afimoxifene|4-hydroxytamoxifen]].{{cn|date=January 2025}}

The [[Crystal structure|crystallographic structure]] of 4-hydroxytamoxifen<ref name="Morello_2012">{{cite journal | vauthors = Morello KC, Wurz GT, DeGregorio MW | title = Pharmacokinetics of selective estrogen receptor modulators | journal = Clinical Pharmacokinetics | volume = 42 | issue = 4 | pages = 361–72 | date = 2012-09-30 | pmid = 12648026 | doi = 10.2165/00003088-200342040-00004 | s2cid = 13003168 }}</ref> interacts with the amino acids of the ER within the ligand-binding domain.<ref name="de_Médina_2004">{{cite journal | vauthors = de Médina P, Favre G, Poirot M | title = Multiple targeting by the antitumor drug tamoxifen: a structure-activity study | journal = Current Medicinal Chemistry. Anti-Cancer Agents | volume = 4 | issue = 6 | pages = 491–508 | date = Nov 2004 | pmid = 15579015 | doi = 10.2174/1568011043352696 | url = https://www.hal.inserm.fr/inserm-00090772 }}</ref> The contact between the phenolic group, water molecule, and glutamate and arginine in the receptor (ERα; Glu 353/Arg 394) resolves in high affinity binding so that 4-hydroxy tamoxifen, with a phenolic ring that resembles the A ring of 17β-estradiol, has more than 100 times higher relative binding affinity than tamoxifen, which has no phenol. If its OH group is eliminated or its position is changed the binding affinity is reduced.<ref name="Miller_2002" /><ref name="Fang_2001" />

The triphenylethylene moiety and the side chain are required for tamoxifen binding to the ER, whereas for 4-hydroxytamoxifen, the side chain, and the phenyl-propene do not appear as crucial structural elements for binding to the ER. The basicity and length of the side chain do not seem to play a crucial role for tamoxifen binding affinity to the ER nor the β-ring of tamoxifen, but the stilbene moiety of tamoxifen is necessary for binding to the ER. The hydroxyl group is of particular importance for ER binding of 4-hydroxytamoxifen, and the ethyl side chain of tamoxifen protrudes out of the ligand-binding domain of the ER.<ref name="de_Médina_2004" />

Few tamoxifen users have had increased rates of uterine cancer, hot flushes, and thromboembolisms. The drug can also cause hepatocarcinomas in rats. This is likely due to the ethyl group of the tamoxifen stilbene core that is subject to [[Allylic oxidation|allylic oxidative]] activation causing DNA [[alkylation]] and strand scission. This problem is later corrected in toremifene.<ref name="Miller_2002" /> Tamoxifen is more promiscuous than raloxifene in target sites because of the relationship between ER's amino acid in Asp-351 and the antiestrogenic side chain of the SERM. The side chain for tamoxifen cannot neutralize Asp-351, so the site [[allosterically]] influences AF-1 at the proximal end of the ER. This issue is mended with the second-generation drug raloxifene.<ref name="Jensen_2003" />

[[Image:Toremifene2DACS.svg|thumb|175px|left|class=skin-invert-image|Chemical structure of toremifene]]

Toremifene is a chlorinated derivative of the nonsteroidal triphenylethylene antiestrogen tamoxifen<ref name="Miller_2002" /> with a chloro substituent at the ethylene side chain producing similar binding affinities to that of tamoxifen.<ref name="Fang_2001" /> The structure and activity relationship of toremifene is similar to that of tamoxifen, but it has a substantial improvement from the older drug in regards to DNA alkylation. The presence of the added chlorine atom reduces the stability of [[cation]]s formed from activated allylic metabolites and thus decreases alkylation potential, and indeed toremifene does not display DNA adduct formation in rodent [[hepatocyte]]s. Toremifene protects against bone loss in ovariectomized rat models and affects bone resorption markers clinically in a similar fashion to tamoxifen.<ref name="Miller_2002" /> Toremifene undergoes phase I metabolism by microsomal cytochrome P450 enzymes, like tamoxifen, but primarily by the CYP3A4 isoform. Toremifene forms its two major metabolites N-desmethyltoremifene and [[Ospemifene|deaminohydroxy-toremifene (ospemifene)]] by undergoing [[N-demethylation]] and deamination-hydroxylation. N-desmethyltoremifene has similar efficacy as toremifene while 4-hydroxytoremifene has a higher binding affinity to the ER than toremifene.<ref name="Morello_2012" /> 4-hydroxytoremifene has a role similar to that of 4-hydroxytamoxifen.<ref>{{cite journal | vauthors = Gauthier S, Mailhot J, Labrie F | title = New Highly Stereoselective Synthesis of (Z)-4-Hydroxytamoxifen and (Z)-4-Hydroxytoremifene via McMurry Reaction | journal = The Journal of Organic Chemistry | volume = 61 | issue = 11 | pages = 3890–3893 | date = May 1996 | pmid = 11667248 | doi = 10.1021/jo952279l }}</ref>

==== Second-generation benzothiophenes ====
[[Image:Raloxifene Chemical Structure V 3.png|thumb|272x272px|class=skin-invert-image|Raloxifene has a benzothiophene group (red) and is connected with a flexible carbonyl hinge to a phenyl 4-piperidinoethoxy side chain (green).]]

Raloxifene belongs to the second-generation [[benzothiophene]] SERM drugs. It has a high affinity for the ER with potent antiestrogenic activity and tissue-specific effects distinct from estradiol.<ref name="Musa_2007" /> Raloxifene is an ER agonist in bone and the cardiovascular system, but in breast tissue and the endometrium it acts as an ER antagonist. It is extensively metabolized by [[glucuronide conjugation]] in the gut and because of that has a low [[bioavailability]] of only 2% while that of tamoxifen and toremifene is approximately 100%.<ref name="Morello_2012" />

The advantage of raloxifene over the triphenylethylene tamoxifen is reduced effect on the uterus. The flexible hinge group, as well as the antiestrogenic phenyl 4-piperidinoethoxy side chain, are important for minimizing uterine effects. Because of its flexibility the side chain can obtain an orthogonal disposition relative to the core<ref name="Miller_2002" /> so that the amine of raloxifene side chain is 1 Å closer than tamoxifens to amino acid Asp-351 in ERα's ligand-binding domain.<ref name="Jensen_2003" /><ref name="Jordan_2003">{{cite journal | vauthors = Jordan VC | title = Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents | journal = Journal of Medicinal Chemistry | volume = 46 | issue = 7 | pages = 1081–111 | date = Mar 2003 | pmid = 12646017 | doi = 10.1021/jm020450x }}</ref>

The critical role of the intimate relationship between the hydrophobic side chain of raloxifene and the hydrophobic residue of the receptor to change both the shape and charge of the external surface of a SERM-ER complex has been confirmed with raloxifene derivatives. When the interactive distance between raloxifene and Asp-351 is increased from 2.7 Å to 3.5-5 Å it causes increased estrogen-like action of the raloxifene-ERα complex. When the piperidine ring of raloxifene is replaced by [[cyclohexane]], the ligand loses antiestrogenic properties and becomes a full agonist. The interaction between SERM's antiestrogenic side chain and amino acid Asp-351 is the important first step in silencing AF-2. It relocates helix 12 away from the ligand-binding pocket thereby preventing coactivators from binding to the SERM-ER complex.<ref name="Jensen_2003" /><ref name="Jordan_2003" />

==== Third-generation ====
[[File:Nafoxidine3.png|thumb|150px|left|class=skin-invert-image|Chemical structure of nafoxidine with the dihydronapthalene group in red.]]
Third-generation compounds display either no uterine stimulation, improved potency, no significant increases in hot flushes or a combination of these attributes.<ref name="Miller_2002" />

The first dihydronapthalene SERM, [[nafoxidine]], was a clinical candidate for the treatment of breast cancer but had side effects including severe phototoxicity. Nafoxidine has all three phenyls constrained in a coplanar arrangement like tamoxifen. But with hydrogenation, the double bond of nafoxidene were reduced, and both phenyls are cis-oriented. The amine-bearing side chain can then adopt an axial conformation and locate this group orthogonally to the plane of the core, like ralofoxifene and other less uterotropic SERMs.{{cn|date=January 2025}}

[[File:Lasofoxifene.png|thumb|150px|class=skin-invert-image|Chemical structure of lasofoxifene shows cis-oriented phenyls.]]

Modifications of nafoxidine resulted in lasofoxifene. Lasofoxifene is among the most potent SERMs reported in protection against bone loss and cholesterol reduction. The excellent oral potency of lasofoxifene has been attributed to reduced intestinal glucuronidation of the phenol.<ref name="Miller_2002" /> Unlike raloxifene, lasofoxifene satisfies the requirement of a [[pharmacophore]] model that predicts resistance to gut wall glucuronidation. The structural requirement is a non-planar topology with the steric bulk close to the plane of a fused bicyclic aromatic system.<ref name="Vajdos_2007">{{cite journal | vauthors = Vajdos FF, Hoth LR, Geoghegan KF, Simons SP, LeMotte PK, Danley DE, Ammirati MJ, Pandit J | title = The 2.0 A crystal structure of the ERalpha ligand-binding domain complexed with lasofoxifene | journal = Protein Science | volume = 16 | issue = 5 | pages = 897–905 | date = May 2007 | pmid = 17456742 | doi = 10.1110/ps.062729207 | pmc=2206632}}</ref> The interactions between the ER and lasofoxifene are consistent with the general features of SERM-ER recognition. Lasofoxifene's large flexible side chain terminates in a pyrrolidine head group and threads its way out toward the surface of the protein, where it interferes directly with the positioning of the AF-2 helix. A salt bridge forms between lasofoxifene and Asp-351. The charge neutralization in this region ER may explain some antiestrogenic effects exerted by lasofoxifene.<ref name=Rosano_2011 />

[[File:Bazedoxifene 2.png|thumb|200px|left|class=skin-invert-image|Bazedoxifene includes an indole system (red) which is connected to an amine through a benzyloxyethyl chain (green).]]

The [[Indole|indole system]] has served as a core unit in SERMs, and when an amine is attached to the indole with a benzyloxyethyl, the resultant compounds were shown to have no preclinical uterine activity while sparing rat bone with full efficacy at low doses. Bazedoxifene is one of those compounds. The core binding domain consists of a 2-phenyl-3-methyl indole and a hexamethylenamine ring at the side chain affecter region. It is metabolized by glucuronidation, with the absolute bioavailability of 6.2%, 3-fold higher than that of raloxifene. It has agonistic effects on bone and lipid metabolism but not on breast and uterine endometrium.<ref name="Kung2009">{{cite journal | vauthors = Kung AW, Chu EY, Xu L | title = Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis | journal = Expert Opinion on Pharmacotherapy | volume = 10 | issue = 8 | pages = 1377–85 | date = Jun 2009 | pmid = 19445558 | doi = 10.1517/14656560902980228 | s2cid = 20781017 }}</ref> It is well tolerated and displays no increase in hot flush {{not a typo|incidences}}, uterine hypertrophy or breast tenderness.<ref name="Miller_2002" />

[[File:Ospemifene 2.png|thumb|200px|class=skin-invert-image|Chemical structure of ospemifene. Ethoxy side chain ends with a hydroxy group (red) instead of a dimethylamino group as with first-generation SERMs.]]

Ospemifene is a triphenylethylene and a known metabolite of toremifene. It's structurally very similar to tamoxifen and toremifene. Ospemifene does not have 2-(dimethylamino)ethoxy group as tamoxifen. Structure–activity relationship studies showed that by removing that group of tamoxifen agonistic activity in the uterus was significantly reduced, but not in bone and cardiovascular system. Preclinical and clinical data show that ospemifene is well tolerated with no major side effects. Benefits that ospemifene may have over other SERMs is its neutral effect on hot flushes and ER-agonist effect on the vagina, improving the symptoms of vaginal dryness.<ref>{{cite journal | vauthors = Gennari L, Merlotti D, Valleggi F, Nuti R | title = Ospemifene use in postmenopausal women | journal = Expert Opinion on Investigational Drugs | volume = 18 | issue = 6 | pages = 839–49 | date = Jun 2009 | pmid = 19466874 | doi = 10.1517/13543780902953715 | s2cid = 21537130 }}</ref>

=== Binding modes ===
[[Image:Estradiol ring system.svg|thumb|left|class=skin-invert-image|The ABCD steroid ring system in 17β-estradiol.]]

The SERMs are known to feature four distinctive modes of binding to ER. One of those features are strong [[hydrogen bonds]] between the ligand and ERα's Arg-394 and Glu-353 that line the "A-ring pocket" and help the ligand to stay in ER's binding pocket. This is unlike 17β-estradiol which is hydrogen bonded to His-524 in the "D-ring pocket".<ref name="Nilsson_2011" /> Other distinctive bindings to the ligand-binding pocket are with a nearly planar "core" structure typically composed of a biaryl [[heterocycle]], equivalent to the A-ring and B-ring of 17β-estradiol, to the corresponding binding site; a bulky side chain from the [[biaryl]] structure, analogous to the B-ring of 17β-estradiol and finally a second side group that is the C- and D-ring equivalent and usually aromatic, fills the remainder volume of the ligand-binding pocket.<ref name="Vajdos_2007" />

The small differences between the two subtypes of ER have been used to develop subtype-selective ER modulators, but the high similarity between the two receptors make the development very challenging. Amino acids in the ligand-binding domains differ at two positions, Leu-384 and Met-421 in ERα and Met-336 and Ile-373 in ERβ, but they have similar hydrophobicity and occupying volumes. However, the shapes and the rotational barrier of the amino acid residues are not the same, leading to distinguish α- and β-face of the binding cavity between ERα and ERβ. This causes ERα-preferential-binding of ligand [[substituent]]s that are aligned downwards facing Met-336 while ligand substituents aligned upwards facing Met-336 are more likely to bind to ERβ. Another difference is in Val-392 in ERα, which is replaced by Met-344 in ERβ. ERβ's binding pocket volume is slightly smaller and the shape a bit different from ERα's. Many ERβ-selective ligands have a largely planar arrangement as the binding cavity of ERβ is slightly narrower than that of ERα, however, this by itself leads to modest selectivity. To attain strong selectivity, the ligand must place substituents very close to one or more of the amino acid differences between ERα and ERβ in order to create a strong repulsive force towards the other subtype receptor. In addition, the structure of the ligand must be rigid. Repulsive interactions may otherwise lead to the conformational change of the ligand and, therefore, create alternative binding modes.<ref name=Nilsson_2011 />

==== First-generation triphenylethylenes ====
Tamoxifen is converted by the liver [[cytochrome P450]] into the 4-hydroxytamoxifen<ref name=Rosano_2011 /> and is a more selective antagonist of the ERα subtype than ERβ.<ref name="Taneja_2006">{{cite journal | vauthors = Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA | title = Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy | journal = Expert Opinion on Investigational Drugs | volume = 15 | issue = 3 | pages = 293–305 | date = Mar 2006 | pmid = 16503765 | doi = 10.1517/13543784.15.3.293 | s2cid = 29510508 }}</ref> 4-hydroxytamoxifen binds to ERs within the same binding pocket that recognizes 17β-estradiol. The receptor recognition of 4-hydroxytamoxifen appears to be controlled by two structural features of 4-hydroxytamoxifen, the phenolic A ring, and the bulky side chain. The phenolic A ring forms hydrogen bonds to the side groups of ER's Arg-394, Glu-354 and to structurally conserved water. The bulky side chain, protruding from the binding cavity, displaces helix 12 from ligand-binding pocket to cover part of the coactivator binding pocket. The ER-4-hydroxytamoxifen complex formation recruits corepressors proteins. This leads to decreased DNA synthesis and inhibition of estrogen activity.<ref name=Rosano_2011 /> Clomifene and torimefene produce binding affinities similar to that of tamoxifen.<ref name="Fang_2001"/> Thus, these two drugs are more selective antagonists of the ERα subtype than ERβ.<ref name="Taneja_2006" />

==== Second-generation benzothiophenes ====
[[File:Raloxifene AnDring.png|thumb|385x385px|class=skin-invert-image|"A ring" (A) and "D ring" (D) marked in raloxifene.]]

Raloxifene, like 4-hydroxytamoxifen, binds to ERα with the hydroxyl group of its phenolic "A ring" through hydrogen bonds with Arg-394 and Glu-353. In addition to these bonds, raloxifene forms a second hydrogen bond to ER through the side group of His-524 because of the presence of a second hydroxyl group in the "D ring". This hydrogen bond is also unlike that between 17β-estradiol and His-524, as the [[imidazole ring]] of His-524 is rotated to counteract the difference of the oxygen position in raloxifene and in 17β-estradiol. Just like in 4-hydroxytamoxifen, the bulky side chain of raloxifene displaces helix 12.<ref name=Rosano_2011 />

==== Third-generation ====
Lasofoxifene interaction with ERα is typical of those between SERM-ERα such as a nearly planar [[topology]] (the tetrahydronapthalene carbocycle), hydrogen bonding with Arg-394 and Glu-353 and the phenyl side chains of lasofoxifene filling the C-ring and D-ring volume of the ligand-binding pocket. Lasofoxifene diverts helix 12 and prevents the binding of coactivator proteins with LXXLL motives. This is achieved by lasofoxifene occupying the space normally filled by Leu-540's side group and modulating the conformation of residues of helix 11 (His-524, Leu-525). Furthermore, lasofoxifene also directly interferes with helix 12 positioning by the drug's ethyl [[Pyrrolidine|pyrrolidine group]].<ref name=Rosano_2011 /> In vitro studies indicate that bazedoxifene competitively blocks 17β-estradiol by high and similar binding to both ERα and ERβ.<ref>{{cite book | editor-last1 = Sanchez | editor-first1 = Antonio Cano | editor-last2 = Calaf i Alsina | editor-first2 = Joaquin | editor-last3 = Dueñas-Díez | editor-first3 = José-Luis | title = Selective estrogen receptor modulators a new brand of multitarget drugs | date = 2006 | publisher = Springer | location = Berlin | isbn = 978-3-540-24227-7 | edition = 1st | pages = 282–3 | first = Santiago | last = Palacios | name-list-style = vanc | chapter = Endometrial Effects of SERMs | chapter-url = https://books.google.com/books?id=heJDAAAAQBAJ&q=bazedoxifene&pg=PA283 | doi = 10.1007/3-540-34742-9_11 }}</ref> Bazedoxifenes main binding domain consists of the 2-phenyl-3-methylindole and a hexamethylenamine ring at the side chain affected region.<ref name=Kung2009 />

Ospemifene is an oxidative deaminated metabolite of toremifene as has a similar binding to ER as toremifene and tamoxifen. The competitive binding to ERα and ERβ of the three metabolites 4-hydroxy Ospemifene, 4'-hydroxy Ospemifene and the 4-hydroxy-, side chain carboxylic acid Ospemifene is at least as high as the parent compound.<ref>{{cite web | publisher = The European Medicines Agency (EMA) | title = Senshio (ospemifene) | url = http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002780/human_med_001837.jsp&mid=WC0b01ac058001d124 | access-date = 2015-11-02 | archive-date = 2018-06-20 | archive-url = https://web.archive.org/web/20180620173809/http://www.ema.europa.eu/ema//index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F002780%2Fhuman_med_001837.jsp&mid=WC0b01ac058001d124 | url-status = dead }}</ref>

== History ==
[[File:Selective estrogen receptor modulator timeline.svg|thumb|284x284px|class=skin-invert-image|Timeline of when SERMs came on the market.]]
The discovery of SERMs resulted from attempts to develop new contraceptives. [[Clomifene]] and [[tamoxifen]] prevented conception in rats but did the opposite in humans. Clomifene successfully induced ovulation in [[subfertile women]] and on February 1, 1967, it was approved in the US for the treatment of [[Ovulation#Disorders|ovulation dysfunction]] in women who were trying to conceive.<ref name="Pickar_2015">{{cite journal | vauthors = Pickar JH, Komm BS | title = Selective estrogen receptor modulators and the combination therapy conjugated estrogens/bazedoxifene: A review of effects on the breast | journal = Post Reproductive Health | volume = 21 | issue = 3 | pages = 112–21 | date = Sep 2015 | pmid = 26289836 | doi = 10.1177/2053369115599090 | s2cid = 206825977 }}</ref> [[Toxicological]] issues prevented long term use of clomifene and further drug development for other potential applications such as [[breast cancer]] treatment and prevention.<ref name="Mirkin_2015">{{cite journal |vauthors = Mirkin S, Pickar JH|title = Selective estrogen receptor modulators (SERMs): a review of clinical data|journal = Maturitas|volume = 80|issue = 1|pages = 52–7|date = Jan 2015|pmid = 25466304|doi = 10.1016/j.maturitas.2014.10.010}}</ref>

It was another ten years before tamoxifen was approved in December 1977, not as a contraceptive but as a hormonal treatment to treat and prevent breast cancer.<ref name="Mirkin_2015" /> The discovery in 1987 that the SERMs tamoxifen and [[raloxifene]], then thought to be [[antiestrogen]]s because of antagonist effects in breast tissue, showed estrogenic effects in preventing bone loss in [[ovariectomized rat]]s had a great effect on our understanding of the function of estrogen receptors and [[nuclear receptor]]s in general.<ref name="Miller_2002">{{cite journal | vauthors = Miller CP | title = SERMs: evolutionary chemistry, revolutionary biology | journal = Current Pharmaceutical Design | volume = 8 | issue = 23 | pages = 2089–111 | year = 2002 | pmid = 12171520 | doi = 10.2174/1381612023393404 }}</ref> The term SERM was introduced to describe these compounds that have a combination of estrogen [[agonist]], partial agonist, or antagonist activities depending on the tissue.<ref name="Pickar_2015" /> Toremifene has been shown to be compatible with tamoxifen, and in 1996 it was approved for use in the treatment of breast cancer in postmenopausal women.<ref>{{cite web | publisher = European Medicines Agency (EMA) | title = Fareston | url = http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000091/human_med_000785.jsp&mid=WC0b01ac058001d124 | access-date = 2015-11-02 | archive-date = 2018-06-20 | archive-url = https://web.archive.org/web/20180620172935/http://www.ema.europa.eu/ema//index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F000091%2Fhuman_med_000785.jsp&mid=WC0b01ac058001d124 | url-status = dead }}</ref>

Raloxifene originally failed as a breast cancer drug due to its poor performance in comparison to tamoxifen in the laboratory<ref name="Musa_2007">{{cite journal |vauthors = Musa MA, Khan MO, Cooperwood JS|title = Medicinal chemistry and emerging strategies applied to the development of selective estrogen receptor modulators (SERMs)|journal = Current Medicinal Chemistry|volume = 14|issue = 11|pages = 1249–61|year = 2007|pmid = 17504144|doi = 10.2174/092986707780598023}}</ref> but the estrogenic effects of raloxifene on bone led to its rediscovery and approval in 1997.<ref name="Mirkin_2015" /> It was approved for prevention and treatment of osteoporosis and was the first clinically available SERM to prevent both osteoporosis and breast cancer.<ref name="Miller_2002" /> [[Ospemifene]] was approved on February 26, 2013, for the treatment of moderate to severe [[dyspareunia]], which is a symptom, due to [[menopause]], of vulvar and vaginal [[atrophy]]. Combined therapy with [[conjugated estrogen]]s and the SERM [[bazedoxifene]], was approved on October 3, 2013, for the treatment of [[vasomotor symptoms]] linked with menopause. Bazedoxifene is also used in the prevention of postmenopausal osteoporosis.<ref name="Mirkin_2015" /> The search for a [[Potency (pharmacology)|potent]] SERM with bone efficacy and better bioavailability than raloxifene led to the discovery of lasofoxifene.<ref name="Rosano_2011">{{cite journal | vauthors = Rosano C, Stec-Martyna E, Lappano R, Maggiolini M | title = Structure-based approach for the discovery of novel selective estrogen receptor modulators | journal = Current Medicinal Chemistry | volume = 18 | issue = 8 | pages = 1188–94 | year = 2011 | pmid = 21291367 | doi = 10.2174/092986711795029645 }}</ref> Although lasofoxifene was approved in 2009, it was not marketed for three years following the approval, so the marketing authorization for it has expired.<ref>{{cite web | title = Fablyn | url = http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000977/human_med_000783.jsp&mid=WC0b01ac058001d124 | publisher = The European Medicines Agency (EMA) | access-date = 2015-11-02 | archive-date = 2018-02-12 | archive-url = https://web.archive.org/web/20180212201605/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F000977%2Fhuman_med_000783.jsp&mid=WC0b01ac058001d124 | url-status = dead }}</ref> In Europe, bazedoxifene is indicated for the treatment of osteoporosis in postmenopausal women at increased risk of fracture. In India, [[ormeloxifene]] has been used for [[dysfunctional uterine bleeding]] and birth control.<ref name="Mirkin_2015" />

== See also ==
* [[Estrogen deprivation therapy]]
* [[List of selective estrogen receptor modulators]]
* [[Selective androgen receptor modulator]]
* [[Selective estrogen receptor degrader]]
* [[Selective receptor modulator]]
* [[Timeline of cancer treatment development]]

== References ==
{{Reflist}}

==External links==
{{Commons category|Selective estrogen receptor modulators}}
* [https://web.archive.org/web/20061215035151/http://www.aacr.org/home/public--media/for-the-media/fact-sheets/cancer-concepts/serms.aspx AACR Cancer Concepts Factsheet on SERMs]
* [https://web.archive.org/web/20070611194336/http://www.nsabp.pitt.edu/STAR/Index.html STAR: a head-to-head comparison of tamoxifen and raloxifene as breast-cancer preventatives]
* [http://www.femarelle.com Femarelle official site]
* [http://www.evista.com Raloxifene (Evista) official site]

{{Estrogens and antiestrogens}}
{{Estrogen receptor modulators}}

[[Category:Hormonal antineoplastic drugs]]
[[Category:Progonadotropins]]
[[Category:Selective estrogen receptor modulators| ]]