Chlorotrianiseneのソースを表示

{{Short description|Chemical compound}}
{{Drugbox
| Verifiedfields = verified
| Watchedfields = verified
| verifiedrevid = 460033186
| IUPAC_name = 1,1',1<nowiki>''</nowiki>-(2-chloroethene-1,1,2-triyl)tris(4-methoxybenzene); 11-chloro-4,13-dimethoxy-12-(''p''-methoxyphenyl)stilbene
| image = Chlorotrianisene.svg
| width = 225px

<!--Clinical data-->
| tradename = Tace, Estregur, Anisene, Clorotrisin, Merbentyl, Triagen, others
| Drugs.com = {{drugs.com|MTM|chlorotrianisene}}
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = X
| pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
| legal_UK = <!-- GSL / P / POM / CD -->
| legal_US = <!-- OTC / Rx-only -->
| legal_status =
| routes_of_administration = [[Oral administration|By mouth]]<ref name="Martindale" /><ref name="Meikle2003" />
| class = [[Nonsteroidal estrogen]]

<!--Pharmacokinetic data-->
| bioavailability =
| protein_bound =
| metabolism = Mono-''O''-[[demethylation]] ([[liver]] [[CYP450]])<ref name="pmid7295335">{{Cite journal |vauthors=Ruenitz PC, Toledo MM |date=August 1981 |title=Chemical and biochemical characteristics of O-demethylation of chlorotrianisene in the rat |journal=Biochem. Pharmacol. |volume=30 |issue=16 |pages=2203–7 |doi=10.1016/0006-2952(81)90088-5 |pmid=7295335}}</ref><ref name="Jordan1986">{{Cite book |url=https://books.google.com/books?id=7WmLZfGXST0C&pg=PA212 |title=Estrogen/antiestrogen Action and Breast Cancer Therapy |vauthors=Jordan VC |publisher=Univ of Wisconsin Press |year=1986 |isbn=978-0-299-10480-1 |page=212}}</ref>
| metabolites = [[Desmethylchlorotrianisene]]<ref name="pmid7295335" /><ref name="Jordan1986" />
| elimination_half-life =
| excretion =

<!--Identifiers-->
| IUPHAR_ligand = 7146
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 569-57-3
| ATC_prefix = G03
| ATC_suffix = CA06
| ATC_supplemental =
| PubChem = 11289
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00269
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 10815
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 6V5034L121
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00269
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 3641
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1200761
| synonyms = CTA; Trianisylchloroethylene; tri-''p''-Anisylchloroethylene; TACE; tris(''p''-Methoxyphenyl)-chloroethylene; NSC-10108

<!--Chemical data-->
| C=23 | H=21 | Cl=1 | O=3
| SMILES = COc1ccc(C(Cl)=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C23H21ClO3/c1-25-19-10-4-16(5-11-19)22(17-6-12-20(26-2)13-7-17)23(24)18-8-14-21(27-3)15-9-18/h4-15H,1-3H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = BFPSDSIWYFKGBC-UHFFFAOYSA-N
}}
<!-- Definition and medical uses -->
'''Chlorotrianisene''' ('''CTA'''), also known as '''tri-''p''-anisylchloroethylene''' ('''TACE''') and sold under the brand name '''Tace''' among others, is a [[nonsteroidal estrogen]] related to [[diethylstilbestrol]] (DES) which was previously used in the treatment of [[menopausal symptoms]] and [[estrogen deficiency]] in women and [[prostate cancer]] in men, among other indications, but has since been discontinued and is now no longer available.<ref name="Elks2014">{{Cite book |url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA263 |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies |vauthors=Elks J |date=14 November 2014 |publisher=Springer |isbn=978-1-4757-2085-3 |pages=263–}}</ref><ref name="IndexNominum2000">{{Cite book |url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA219 |title=Index Nominum 2000: International Drug Directory |date=January 2000 |publisher=Taylor & Francis |isbn=978-3-88763-075-1 |pages=219–}}</ref><ref name="MortonHall2012">{{Cite book |url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA73 |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms |vauthors=Morton IK, Hall JM |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-94-011-4439-1 |pages=73–}}</ref><ref name="Martindale">{{Cite book |url=https://www.medicinescomplete.com/mc/martindale/2009/9029-q.htm |title=Martindale: The Complete Drug Reference |publisher=Pharmaceutical Press |year=2009 |isbn=978-0-85369-840-1 |veditors=Sweetman SC |edition=36th |location=London |page=2085 |chapter=Sex hormones and their modulators}}</ref><ref name="pmid7500443">{{Cite journal |vauthors=Cox RL, Crawford ED |date=December 1995 |title=Estrogens in the treatment of prostate cancer |journal=The Journal of Urology |volume=154 |issue=6 |pages=1991–8 |doi=10.1016/S0022-5347(01)66670-9 |pmid=7500443}}</ref> It is taken [[oral administration|by mouth]].<ref name="Martindale" /><ref name="Meikle2003" />

<!-- Side effects and mechanism -->
CTA is an [[estrogen (medication)|estrogen]], or an [[agonist]] of the [[estrogen receptor]]s, the [[biological target]] of estrogens like [[estradiol]].<ref name="MortonHall2012" /><ref name="Martindale" /><ref name="LuniwalJetson2012">{{Cite book |title=Analogue-Based Drug Discovery III |vauthors=Luniwal A, Jetson R, Erhardt P |year=2012 |isbn=9783527651085 |veditors=Fischer J, Ganellin CR, Rotella DP |pages=165–185 |chapter=Selective Estrogen Receptor Modulators |doi=10.1002/9783527651085.ch7}}</ref><ref name="pmid6541293">{{Cite journal |vauthors=Jordan VC, Lieberman ME |date=September 1984 |title=Estrogen-stimulated prolactin synthesis in vitro. Classification of agonist, partial agonist, and antagonist actions based on structure |journal=Molecular Pharmacology |volume=26 |issue=2 |pages=279–85 |pmid=6541293}}</ref> It is a high-[[intrinsic activity|efficacy]] [[partial agonist|partial]] estrogen and shows some properties of a [[selective estrogen receptor modulator]], with predominantly [[estrogen (medication)|estrogen]]ic activity but also some [[antiestrogen]]ic activity.<ref name="FischerGanellin2012" /><ref name="Sneader2005" /> CTA itself is inactive and is a [[prodrug]] in the body.<ref name="Meikle2003" /><ref name="Hadden2013" />

<!-- History, society, and culture -->
CTA was introduced for medical use in 1952.<ref name="Publishing2013" /> It has been marketed in the [[United States]] and [[Europe]].<ref name="Publishing2013" /><ref name="IndexNominum2000" /> However, it has since been discontinued and is no longer available in any country.<ref name="Martindale" /><ref name="Micromedex" />

==Medical uses==
CTA has been used in the treatment of [[menopausal symptoms]] and [[estrogen deficiency]] in women and [[prostate cancer]] in men, among other indications.<ref name="MortonHall2012" /><ref name="Martindale" /> It has been used to suppress [[lactation]] in women.<ref name="Vorherr2012">{{Cite book |url=https://books.google.com/books?id=wYxirvD2X2IC&pg=PA203 |title=The Breast: Morphology, Physiology, and Lactation |vauthors=Vorherr H |date=2 December 2012 |publisher=Elsevier Science |isbn=978-0-323-15726-1 |pages=203–}}</ref> CTA has been used in the treatment of [[acne]] as well.<ref name="Schirren1961">{{Cite book |title=Therapie der Haut- und Geschlechtskrankheiten |vauthors=Schirren C |year=1961 |isbn=978-3-642-94851-0 |pages=470–549 |chapter=Die Sexualhormone |doi=10.1007/978-3-642-94850-3_6}}</ref><ref name="pmid13084969">{{Cite journal |vauthors=Kile RL |date=August 1953 |title=The treatment of acne with TACE |journal=J Invest Dermatol |volume=21 |issue=2 |pages=79–81 |doi=10.1038/jid.1953.73 |pmid=13084969 |doi-access=free}}</ref><ref name="pmid13147544">{{Cite journal |vauthors=Welsh AL |date=April 1954 |title=Use of synthetic estrogenic substance chlorotrianisene (TACE) in treatment of acne |journal=AMA Arch Dermatol Syphilol |volume=69 |issue=4 |pages=418–27 |doi=10.1001/archderm.1954.01540160020004 |pmid=13147544}}</ref>

{{Estrogen dosages for breast and prostate cancer}}

==Side effects==
{{See also|Estrogen (medication)#Side effects}}

In men, CTA can produce [[gynecomastia]] as a [[side effect]].<ref name="Dao1975">{{Cite book |title=Antineoplastic and Immunosuppressive Agents |vauthors=Dao TL |year=1975 |isbn=978-3-642-65806-8 |veditors=Sartorelli AC, Johns DG |pages=170–192 |chapter=Pharmacology and Clinical Utility of Hormones in Hormone Related Neoplasms |doi=10.1007/978-3-642-65806-8_11 |chapter-url=https://books.google.com/books?id=aU_oCAAAQBAJ&pg=PA170}}</ref><ref name="Li2009" /> Conversely, it does not appear to lower [[testosterone]] levels in men, and hence does not seem to have a risk of [[hypogonadism]] and associated side effects in men.<ref name="Ghanadian2012" />

==Pharmacology==
[[File:Testosterone levels with different estrogen therapies in men with prostate cancer.png|thumb|right|300px|Testosterone levels with no treatment and with various estrogens in men with prostate cancer.<ref name="pmid4359746">{{Cite journal |vauthors=Shearer RJ, Hendry WF, Sommerville IF, Fergusson JD |date=December 1973 |title=Plasma testosterone: an accurate monitor of hormone treatment in prostatic cancer |journal=Br J Urol |volume=45 |issue=6 |pages=668–77 |doi=10.1111/j.1464-410x.1973.tb12238.x |pmid=4359746}}</ref> Determinations were made with an early [[radioimmunoassay]] (RIA).<ref name="pmid4359746" /> Source was Shearer et al. (1973).<ref name="pmid4359746" />]]

CTA is a relatively weak [[estrogen (medication)|estrogen]], with about one-eighth the potency of DES.<ref name="Meikle2003" /><ref name="Sneader2005" /> However, it is highly [[lipophilic]] and is stored in [[fat tissue]] for prolonged periods of time, with its slow release from fat resulting in a very long duration of action.<ref name="Meikle2003" /><ref name="Sneader2005" /><ref name="pmid3905383" /> CTA itself is inactive; it behaves as a [[prodrug]] to [[desmethylchlorotrianisene]] (DMCTA),<ref name="pmid7295335" /><ref name="Jordan1986" /> a weak estrogen that is formed as a [[metabolite]] via mono-''O''-[[demethylation]] of CTA in the [[liver]].<ref name="Meikle2003" /><ref name="Hadden2013">{{Cite book |url=https://books.google.com/books?id=fmfSBwAAQBAJ&pg=PA249 |title=Pharmacology |vauthors=Hadden J |date=9 November 2013 |publisher=Springer Science & Business Media |isbn=978-1-4615-9406-2 |pages=249–}}</ref> As such, the potency of CTA is reduced if it is given [[parenteral]]ly instead of orally.<ref name="Meikle2003" />

Although it is referred to as a weak [[estrogen (medication)|estrogen]] and was used solely as an estrogen in clinical practice, CTA is a high-[[intrinsic activity|efficacy]] [[partial agonist]] of the [[estrogen receptor]].<ref name="Sneader2005" /> As such, it is a [[selective estrogen receptor modulator]] (SERM), with predominantly estrogenic effects but also with [[antiestrogen]]ic effects, and was arguably the first SERM to ever be introduced.<ref name="FischerGanellin2012">{{Cite book |url=https://books.google.com/books?id=BP2Bo11gTOMC&pg=SA5-PA56 |title=Analogue-based Drug Discovery III |vauthors=Fischer J, Ganellin CR, Rotella DP |date=15 October 2012 |publisher=John Wiley & Sons |isbn=978-3-527-65110-8 |pages=5–}}</ref> CTA can antagonize [[estradiol]] at the level of the [[hypothalamus]], resulting in disinhibition of the [[hypothalamic–pituitary–gonadal axis]] and an increase in estrogen levels.<ref name="Sneader2005" /> [[Clomifene]] and [[tamoxifen]] were both derived from CTA via [[structural modification]], and are much lower-efficacy partial agonists than CTA and hence much more antiestrogenic in comparison.<ref name="Sneader2005" /><ref name="LuniwalJetson2012" /> As an example, chlorotrianisene produces [[gynecomastia]] in men,<ref name="Li2009">{{Cite book |url=https://books.google.com/books?id=-GPl1PA5EgMC&pg=PA34 |title=Triumph of the Heart: The Story of Statins |vauthors=Li JJ |date=3 April 2009 |publisher=Oxford University Press, USA |isbn=978-0-19-532357-3 |pages=34–}}</ref> albeit reportedly to a lesser extent than other estrogens,<ref>{{Cite book |url=https://books.google.com/books?id=5ZbLRONHoDoC&pg=PA387 |title=Vitamins and Hormones |date=18 May 1976 |publisher=Academic Press |isbn=978-0-08-086630-7 |pages=387–}}</ref> while clomifene and tamoxifen do not and can be used to treat gynecomastia.<ref name="Khan2003">{{Cite journal |vauthors=Khan HN, Blamey RW |date=August 2003 |title=Endocrine treatment of physiological gynaecomastia |journal=BMJ |volume=327 |issue=7410 |pages=301–2 |doi=10.1136/bmj.327.7410.301 |pmc=1126712 |pmid=12907471}}</ref>

CTA at a dosage of 48&nbsp;mg/day inhibits [[ovulation]] in almost all women.<ref name="pmid13370006">{{Cite journal |vauthors=Duncan CJ, Kistner RW, Mansell H |date=October 1956 |title=Suppression of ovulation by trip-anisyl chloroethylene (TACE) |url=https://journals.lww.com/greenjournal/citation/1956/10000/suppression_of_ovulation_by_tri_p_anisyl.4.aspx |journal=Obstet Gynecol |volume=8 |issue=4 |pages=399–407 |pmid=13370006}}</ref> Conversely, it has been reported that CTA has no measurable effect on circulating levels of [[testosterone]] in men.<ref name="Ghanadian2012">{{Cite book |url=https://books.google.com/books?id=8mkyBwAAQBAJ&pg=PA70 |title=The Endocrinology of Prostate Tumours |vauthors=Ghanadian R |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-94-011-7256-1 |pages=70–}}</ref> This is in contrast to other estrogens, like [[diethylstilbestrol]], which can suppress testosterone levels by as much as 96%—or to an equivalent extent as [[castration]].<ref name="Ghanadian2012" /> These findings suggest that CTA is not an effective [[antigonadotropin]] in men.<ref name="Ghanadian2012" />

==Chemistry==
Chlorotrianisene, also known as tri-''p''-anisylchloroethylene (TACE) or as tris(''p''-methoxyphenyl)chloroethylene, is a [[synthetic compound|synthetic]] [[nonsteroidal]] [[chemical compound|compound]] of the [[triphenylethylene]] group.<ref name="Elks2014" /><ref name="MortonHall2012" /><ref name="Martindale" /> It is structurally related to the nonsteroidal estrogen [[diethylstilbestrol]] and to the SERMs [[clomifene]] and [[tamoxifen]].<ref name="Martindale" /><ref name="Sneader2005" /><ref name="LuniwalJetson2012" />

==History==
CTA was introduced for medical use in the [[United States]] in 1952, and was subsequently introduced for use throughout [[Europe]].<ref name="Publishing2013">{{Cite book |last=William Andrew Publishing |url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA980 |title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition |date=22 October 2013 |publisher=Elsevier |isbn=978-0-8155-1856-3 |pages=980–}}</ref><ref name="IndexNominum2000" /> It was the first [[estrogen (medication)|estrogen]]ic compound of the triphenylethylene series to be introduced.<ref name="FischerGanellin2012" /> CTA was derived from [[estrobin]] (DBE), a [[chemical derivative|derivative]] of the very weakly estrogenic compound [[triphenylethylene]] (TPE), which in turn was derived from structural modification of [[diethylstilbestrol]] (DES).<ref name="Meikle2003">{{Cite book |url=https://books.google.com/books?id=CA0HCAAAQBAJ&pg=PA486 |title=Endocrine Replacement Therapy in Clinical Practice |vauthors=Meikle AW |date=24 April 2003 |publisher=Springer Science & Business Media |isbn=978-1-59259-375-0 |pages=486–}}</ref><ref name="Sneader2005">{{Cite book |url=https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA198 |title=Drug Discovery: A History |vauthors=Sneader W |date=23 June 2005 |publisher=John Wiley & Sons |isbn=978-0-471-89979-2 |pages=198–}}</ref><ref name="pmid3905383">{{Cite journal |vauthors=Jordan VC, Mittal S, Gosden B, Koch R, Lieberman ME |date=September 1985 |title=Structure-activity relationships of estrogens |journal=Environmental Health Perspectives |volume=61 |pages=97–110 |bibcode=1985EnvHP..61...97J |doi=10.1289/ehp.856197 |pmc=1568776 |pmid=3905383}}</ref><ref name="AvendanoMenendez2015">{{Cite book |url=https://books.google.com/books?id=VEibBwAAQBAJ&pg=PA87 |title=Medicinal Chemistry of Anticancer Drugs |vauthors=Avendano C, Menendez JC |date=11 June 2015 |publisher=Elsevier Science |isbn=978-0-444-62667-7 |pages=87–}}</ref> The SERMs [[clomifene]] and [[tamoxifen]], as well as the [[antiestrogen]] [[ethamoxytriphetol]], were derived from CTA via structural modification.<ref name="Sneader2005" /><ref name="LuniwalJetson2012" /><ref name="Manni1999">{{Cite book |url=https://books.google.com/books?id=7DSYBwAAQBAJ&pg=PA286 |title=Endocrinology of Breast Cancer |vauthors=Manni A |date=15 January 1999 |publisher=Springer Science & Business Media |isbn=978-1-59259-699-7 |pages=286–287}}</ref><ref name="Ravina2011">{{Cite book |url=https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA178 |title=The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs |vauthors=Ravina E |date=11 January 2011 |publisher=John Wiley & Sons |isbn=978-3-527-32669-3 |pages=178–}}</ref>

==Society and culture==

===Generic names===
''Chlorotrianisene'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|BAN|British Approved Name}}.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" /> It is also known as ''tri-p-anisylchloroethylene'' (''TACE'').<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" />

===Brand names===
CTA has been marketed under the brand names Tace, Estregur, Anisene, Clorotrisin, Merbentyl, Merbentul, and Triagen among many others.<ref name="Elks2014" /><ref name="IndexNominum2000" />

===Availability===
CTA is no longer marketed and hence is no longer available in any country.<ref name="Martindale" /><ref name="Micromedex">http://www.micromedexsolutions.com/micromedex2/{{Dead link|date=June 2019 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> It was previously used in the [[United States]] and [[Europe]].<ref name="Publishing2013" /><ref name="IndexNominum2000" />

==References==
{{Reflist}}

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

[[Category:Abandoned drugs]]
[[Category:Hormonal antineoplastic drugs]]
[[Category:Organochlorides]]
[[Category:4-Methoxyphenyl compounds]]
[[Category:Prodrugs]]
[[Category:Progonadotropins]]
[[Category:Selective estrogen receptor modulators]]
[[Category:Synthetic estrogens]]
[[Category:Triphenylethylenes]]
[[Category:Bis(4-hydroxyphenyl)methanes]]