Chemistry:Chlorotrianisene

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Short description: Chemical compound
Chlorotrianisene
Chlorotrianisene.svg
Clinical data
Trade namesTace, Estregur, Anisene, Clorotrisin, Merbentyl, Triagen, others
Other namesCTA; Trianisylchloroethylene; tri-p-Anisylchloroethylene; TACE; tris(p-Methoxyphenyl)-chloroethylene; NSC-10108
AHFS/Drugs.comMultum Consumer Information
Pregnancy
category
  • US: X (Contraindicated)
Routes of
administration		By mouth[1][2]
Drug classNonsteroidal estrogen
ATC code
Pharmacokinetic data
MetabolismMono-O-demethylation (liver CYP450)[3][4]
MetabolitesDesmethylchlorotrianisene[3][4]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC23H21ClO3
Molar mass380.87 g·mol−1
3D model (JSmol)
  (verify)

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.[5][6][7][1][8] It is taken by mouth.[1][2]

CTA is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol.[7][1][9][10] It is a high-efficacy partial estrogen and shows some properties of a selective estrogen receptor modulator, with predominantly estrogenic activity but also some antiestrogenic activity.[11][12] CTA itself is inactive and is a prodrug in the body.[2][13]

CTA was introduced for medical use in 1952.[14] It has been marketed in the United States and Europe.[14][6] However, it has since been discontinued and is no longer available in any country.[1][15]

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.[7][1] It has been used to suppress lactation in women.[16] CTA has been used in the treatment of acne as well.[17][18][19]

v · d · e Estrogen dosages for prostate cancer
Route/form Estrogen Dosage
Oral Estradiol 1–2 mg 3x/day
Conjugated estrogens 1.25–2.5 mg 3x/day
Ethinylestradiol 0.15–3 mg/day
Ethinylestradiol sulfonate 1–2 mg 1x/week
Diethylstilbestrol 1–3 mg/day
Dienestrol 5 mg/day
Hexestrol 5 mg/day
Fosfestrol 100–480 mg 1–3x/day
Chlorotrianisene 12–48 mg/day
Quadrosilan 900 mg/day
Estramustine phosphate 140–1400 mg/day
Transdermal patch Estradiol 2–6x 100 μg/day
Scrotal: 1x 100 μg/day
IM or SC injection Estradiol benzoate 1.66 mg 3x/week
Estradiol dipropionate 5 mg 1x/week
Estradiol valerate 10–40 mg 1x/1–2 weeks
Estradiol undecylate 100 mg 1x/4 weeks
Polyestradiol phosphate Alone: 160–320 mg 1x/4 weeks
With oral EE: 40–80 mg 1x/4 weeks
Estrone 2–4 mg 2–3x/week
IV injection Fosfestrol 300–1200 mg 1–7x/week
Estramustine phosphate 240–450 mg/day
Note: Dosages are not necessarily equivalent. Sources: See template.

Side effects

In men, CTA can produce gynecomastia as a side effect.[20][21] 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.[22]

Pharmacology

Testosterone levels with no treatment and with various estrogens in men with prostate cancer.[23] Determinations were made with an early radioimmunoassay (RIA).[23] Source was Shearer et al. (1973).[23]

CTA is a relatively weak estrogen, with about one-eighth the potency of DES.[2][12] 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.[2][12][24] CTA itself is inactive; it behaves as a prodrug to desmethylchlorotrianisene (DMCTA),[3][4] a weak estrogen that is formed as a metabolite via mono-O-demethylation of CTA in the liver.[2][13] As such, the potency of CTA is reduced if it is given parenterally instead of orally.[2]

Although it is referred to as a weak estrogen and was used solely as an estrogen in clinical practice, CTA is a high-efficacy partial agonist of the estrogen receptor.[12] As such, it is a selective estrogen receptor modulator (SERM), with predominantly estrogenic effects but also with antiestrogenic effects, and was arguably the first SERM to ever be introduced.[11] 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.[12] 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.[12][9] As an example, chlorotrianisene produces gynecomastia in men,[21] albeit reportedly to a lesser extent than other estrogens,[25] while clomifene and tamoxifen do not and can be used to treat gynecomastia.[26]

CTA at a dosage of 48 mg/day inhibits ovulation in almost all women.[27] Conversely, it has been reported that CTA has no measurable effect on circulating levels of testosterone in men.[22] 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.[22] These findings suggest that CTA is not an effective antigonadotropin in men.[22]

Chemistry

Chlorotrianisene, also known as tri-p-anisylchloroethylene (TACE) or as tris(p-methoxyphenyl)chloroethylene, is a synthetic nonsteroidal compound of the triphenylethylene group.[5][7][1] It is structurally related to the nonsteroidal estrogen diethylstilbestrol and to the SERMs clomifene and tamoxifen.[1][12][9]

History

CTA was introduced for medical use in the United States in 1952, and was subsequently introduced for use throughout Europe.[14][6] It was the first estrogenic compound of the triphenylethylene series to be introduced.[11] CTA was derived from estrobin (DBE), a derivative of the very weakly estrogenic compound triphenylethylene (TPE), which in turn was derived from structural modification of diethylstilbestrol (DES).[2][12][24][28] The SERMs clomifene and tamoxifen, as well as the antiestrogen ethamoxytriphetol, were derived from CTA via structural modification.[12][9][29][30]

Society and culture

Generic names

Chlorotrianisene is the generic name of the drug and its INN, USAN, and BAN.[5][6][7] It is also known as tri-p-anisylchloroethylene (TACE).[5][6][7]

Brand names

CTA has been marketed under the brand names Tace, Estregur, Anisene, Clorotrisin, Merbentyl, Merbentul, and Triagen among many others.[5][6]

Availability

CTA is no longer marketed and hence is no longer available in any country.[1][15] It was previously used in the United States and Europe.[14][6]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. 2009. p. 2085. ISBN 978-0-85369-840-1. https://www.medicinescomplete.com/mc/martindale/2009/9029-q.htm. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Endocrine Replacement Therapy in Clinical Practice. Springer Science & Business Media. 24 April 2003. pp. 486–. ISBN 978-1-59259-375-0. https://books.google.com/books?id=CA0HCAAAQBAJ&pg=PA486. 
  3. ↑ 3.0 3.1 3.2 "Chemical and biochemical characteristics of O-demethylation of chlorotrianisene in the rat". Biochem. Pharmacol. 30 (16): 2203–7. August 1981. doi:10.1016/0006-2952(81)90088-5. PMID 7295335. 
  4. ↑ 4.0 4.1 4.2 Estrogen/antiestrogen Action and Breast Cancer Therapy. Univ of Wisconsin Press. 1986. p. 212. ISBN 978-0-299-10480-1. https://books.google.com/books?id=7WmLZfGXST0C&pg=PA212. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 263–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA263. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 219–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA219. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 6 December 2012. pp. 73–. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA73. 
  8. ↑ "Estrogens in the treatment of prostate cancer". The Journal of Urology 154 (6): 1991–8. December 1995. doi:10.1016/S0022-5347(01)66670-9. PMID 7500443. 
  9. ↑ 9.0 9.1 9.2 9.3 "Selective Estrogen Receptor Modulators". Analogue-Based Drug Discovery III. 2012. pp. 165–185. doi:10.1002/9783527651085.ch7. ISBN 9783527651085. 
  10. ↑ "Estrogen-stimulated prolactin synthesis in vitro. Classification of agonist, partial agonist, and antagonist actions based on structure". Molecular Pharmacology 26 (2): 279–85. September 1984. PMID 6541293. 
  11. ↑ 11.0 11.1 11.2 Analogue-based Drug Discovery III. John Wiley & Sons. 15 October 2012. pp. 5–. ISBN 978-3-527-65110-8. https://books.google.com/books?id=BP2Bo11gTOMC&pg=SA5-PA56. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8 Drug Discovery: A History. John Wiley & Sons. 23 June 2005. pp. 198–. ISBN 978-0-471-89979-2. https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA198. 
  13. ↑ 13.0 13.1 Pharmacology. Springer Science & Business Media. 9 November 2013. pp. 249–. ISBN 978-1-4615-9406-2. https://books.google.com/books?id=fmfSBwAAQBAJ&pg=PA249. 
  14. ↑ 14.0 14.1 14.2 14.3 William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 980–. ISBN 978-0-8155-1856-3. https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA980. 
  15. ↑ 15.0 15.1 http://www.micromedexsolutions.com/micromedex2/[yes|permanent dead link|dead link}}]
  16. ↑ The Breast: Morphology, Physiology, and Lactation. Elsevier Science. 2 December 2012. pp. 203–. ISBN 978-0-323-15726-1. https://books.google.com/books?id=wYxirvD2X2IC&pg=PA203. 
  17. ↑ "Die Sexualhormone". Therapie der Haut- und Geschlechtskrankheiten. 1961. pp. 470–549. doi:10.1007/978-3-642-94850-3_6. ISBN 978-3-642-94851-0. 
  18. ↑ "The treatment of acne with TACE". J Invest Dermatol 21 (2): 79–81. August 1953. doi:10.1038/jid.1953.73. PMID 13084969. 
  19. ↑ "Use of synthetic estrogenic substance chlorotrianisene (TACE) in treatment of acne". AMA Arch Derm Syphilol 69 (4): 418–27. April 1954. doi:10.1001/archderm.1954.01540160020004. PMID 13147544. 
  20. ↑ "Pharmacology and Clinical Utility of Hormones in Hormone Related Neoplasms". Antineoplastic and Immunosuppressive Agents. 1975. pp. 170–192. doi:10.1007/978-3-642-65806-8_11. ISBN 978-3-642-65806-8. https://books.google.com/books?id=aU_oCAAAQBAJ&pg=PA170. 
  21. ↑ 21.0 21.1 Triumph of the Heart: The Story of Statins. Oxford University Press, USA. 3 April 2009. pp. 34–. ISBN 978-0-19-532357-3. https://books.google.com/books?id=-GPl1PA5EgMC&pg=PA34. 
  22. ↑ 22.0 22.1 22.2 22.3 The Endocrinology of Prostate Tumours. Springer Science & Business Media. 6 December 2012. pp. 70–. ISBN 978-94-011-7256-1. https://books.google.com/books?id=8mkyBwAAQBAJ&pg=PA70. 
  23. ↑ 23.0 23.1 23.2 "Plasma testosterone: an accurate monitor of hormone treatment in prostatic cancer". Br J Urol 45 (6): 668–77. December 1973. doi:10.1111/j.1464-410x.1973.tb12238.x. PMID 4359746. 
  24. ↑ 24.0 24.1 "Structure-activity relationships of estrogens". Environmental Health Perspectives 61: 97–110. September 1985. doi:10.1289/ehp.856197. PMID 3905383. 
  25. ↑ Vitamins and Hormones. Academic Press. 18 May 1976. pp. 387–. ISBN 978-0-08-086630-7. https://books.google.com/books?id=5ZbLRONHoDoC&pg=PA387. 
  26. ↑ "Endocrine treatment of physiological gynaecomastia". BMJ 327 (7410): 301–2. August 2003. doi:10.1136/bmj.327.7410.301. PMID 12907471. 
  27. ↑ "Suppression of ovulation by trip-anisyl chloroethylene (TACE)". Obstet Gynecol 8 (4): 399–407. October 1956. PMID 13370006. https://journals.lww.com/greenjournal/citation/1956/10000/suppression_of_ovulation_by_tri_p_anisyl.4.aspx. 
  28. ↑ Medicinal Chemistry of Anticancer Drugs. Elsevier Science. 11 June 2015. pp. 87–. ISBN 978-0-444-62667-7. https://books.google.com/books?id=VEibBwAAQBAJ&pg=PA87. 
  29. ↑ Endocrinology of Breast Cancer. Springer Science & Business Media. 15 January 1999. pp. 286–287. ISBN 978-1-59259-699-7. https://books.google.com/books?id=7DSYBwAAQBAJ&pg=PA286. 
  30. ↑ The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. 11 January 2011. pp. 178–. ISBN 978-3-527-32669-3. https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA178. 



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