Editing Selective estrogen receptor modulator (section)

==== 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>