Editing Selective estrogen receptor modulator (section)

=== 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>