Chlorotrianisene

Last updated
Chlorotrianisene
Chlorotrianisene.svg
Clinical data
Trade names Tace, Estregur, Anisene, Clorotrisin, Merbentyl, Triagen, others
Other namesCTA; Trianisylchloroethylene; tri-p-Anisylchloroethylene; TACE; tris(p-Methoxyphenyl)-chloroethylene; NSC-10108
AHFS/Drugs.com Multum Consumer Information
Routes of
administration 		By mouth [1] [2]
Drug class Nonsteroidal estrogen
ATC code
Pharmacokinetic data
Metabolism Mono-O-demethylation (liver CYP450) [3] [4]
Metabolites Desmethylchlorotrianisene [3] [4]
Identifiers
  • 1,1',1''-(2-chloroethene-1,1,2-triyl)tris(4-methoxybenzene); 11-chloro-4,13-dimethoxy-12-(p-methoxyphenyl)stilbene
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.008.472 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H21ClO3
Molar mass 380.87 g·mol−1
3D model (JSmol)
  • COc1ccc(C(Cl)=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
  • InChI=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 Yes check.svgY
  • Key:BFPSDSIWYFKGBC-UHFFFAOYSA-N Yes check.svgY
   (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]

Contents

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]

Estrogen dosages for prostate cancer
Route/formEstrogenDosage
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
Chlorotrianisene12–48 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 Tooltip Intramuscular 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. Determinations were made with an early radioimmunoassay (RIA). Source was Shearer et al. (1973). Testosterone levels with different estrogen therapies in men with prostate cancer.png
Testosterone levels with no treatment and with various estrogens in men with prostate cancer. Determinations were made with an early radioimmunoassay (RIA). Source was Shearer et al. (1973).

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 Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, and BAN Tooltip British Approved Name. [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]

Related Research Articles

<span class="mw-page-title-main">Clomifene</span> Infertility treatment for women

Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. It is taken by mouth.

<span class="mw-page-title-main">Selective estrogen receptor modulator</span> Drugs acting on the estrogen receptor

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–antagonists, SERMs are more tissue-specific, allowing them to selectively inhibit or stimulate estrogen-like action in various tissues.

<span class="mw-page-title-main">Tamoxifen</span> Medication

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.

<span class="mw-page-title-main">Raloxifene</span> Chemical compound

Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to reduce the risk of breast cancer in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Stilbestrol</span> Chemical compound

Stilbestrol, or stilboestrol, also known as 4,4'-dihydroxystilbene or 4,4'-stilbenediol, is a stilbenoid nonsteroidal estrogen and the parent compound of a group of more potent nonsteroidal estrogen derivatives that includes, most notably, diethylstilbestrol (DES). The term "stilbestrol" is often used incorrectly to refer to DES, but they are not the same compound.

<span class="mw-page-title-main">Toremifene</span> Chemical compound

Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women. It is taken by mouth.

A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents.

<span class="mw-page-title-main">Zuclomifene</span> Chemical compound

Zuclomifene (INN; or zuclomiphene (USAN)) is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was never marketed. It is one of the two stereoisomers of clomifene, which itself is a mixture of 38% zuclomifene and 62% enclomifene. Zuclomifene is the (Z)-stereoisomer of clomifene, while enclomifene is the (E)-stereoisomer. Whereas zuclomifene is described as mildly estrogenic, enclomifene is described as antiestrogenic. In accordance, unlike enclomifene, zuclomifene is antigonadotropic due to activation of the estrogen receptor and reduces testosterone levels in men. It is also about five times more potent than enclomifene in inducing ovulation.

<span class="mw-page-title-main">Afimoxifene</span> Chemical compound

Afimoxifene, also known as 4-hydroxytamoxifen (4-OHT) and by its tentative brand name TamoGel, is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development under the tentative brand name TamoGel as a topical gel for the treatment of hyperplasia of the breast. It has completed a phase II clinical trial for cyclical mastalgia, but further studies are required before afimoxifene can be approved for this indication and marketed.

<span class="mw-page-title-main">Nafoxidine</span> Chemical compound

Nafoxidine or nafoxidine hydrochloride is a nonsteroidal selective estrogen receptor modulator (SERM) or partial antiestrogen of the triphenylethylene group that was developed for the treatment of advanced breast cancer by Upjohn in the 1970s but was never marketed. It was developed at around the same time as tamoxifen and clomifene, which are also triphenylethylene derivatives. The drug was originally synthesized by the fertility control program at Upjohn as a postcoital contraceptive, but was subsequently repurposed for the treatment of breast cancer. Nafoxidine was assessed in clinical trials in the treatment of breast cancer and was found to be effective. However, it produced side effects including ichthyosis, partial hair loss, and phototoxicity of the skin in almost all patients, and this resulted in the discontinuation of its development.

<span class="mw-page-title-main">Nonsteroidal estrogen</span> Class of drugs

A nonsteroidal estrogen is an estrogen with a nonsteroidal chemical structure. The most well-known example is the stilbestrol estrogen diethylstilbestrol (DES). Although nonsteroidal estrogens formerly had an important place in medicine, they have gradually fallen out of favor following the discovery of toxicities associated with high-dose DES starting in the early 1970s, and are now almost never used. On the other hand, virtually all selective estrogen receptor modulators (SERMs) are nonsteroidal, with triphenylethylenes like tamoxifen and clomifene having been derived from DES, and these drugs remain widely used in medicine for the treatment of breast cancer among other indications. In addition to pharmaceutical drugs, many xenoestrogens, including phytoestrogens, mycoestrogens, and synthetic endocrine disruptors like bisphenol A, are nonsteroidal substances with estrogenic activity.

<span class="mw-page-title-main">Broparestrol</span> Chemical compound

Broparestrol, also known as α-bromo-α,β-diphenyl-β-p-ethylphenylethylene (BDPE), is a synthetic, nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that has been used in Europe as a dermatological agent and for the treatment of breast cancer. The drug is described as slightly estrogenic and potently antiestrogenic, and inhibits mammary gland development and suppresses prolactin levels in animals. It is structurally related to clomifene and diethylstilbestrol. Broparestrol is a mixture of E- and Z- isomers, both of which are active, and are similarly antiestrogenic but, unlike broparestrol, were never marketed.

<span class="mw-page-title-main">Triphenylethylene</span> Chemical compound

Triphenylethylene (TPE) is a simple aromatic hydrocarbon that possesses weak estrogenic activity. Its estrogenic effects were discovered in 1937. TPE was derived from structural modification of the more potent estrogen diethylstilbestrol, which is a member of the stilbestrol group of nonsteroidal estrogens.

<span class="mw-page-title-main">Estrobin</span> Chemical compound

Estrobin, also known as α,α-di(p-ethoxyphenyl)-β-phenylbromoethylene and commonly abbreviated as DBE, is a synthetic, nonsteroidal estrogen of the triphenylethylene group that was never marketed. Chlorotrianisene, and subsequently clomifene and tamoxifen, were derived from it. Estrobin, similarly to other triphenylethylenes, is very lipophilic and hence very long-lasting in its duration of action. Similarly to chlorotrianisene, estrobin behaves a prodrug to a much more potent estrogen in the body.

<span class="mw-page-title-main">Ethamoxytriphetol</span> Chemical compound

Ethamoxytriphetol is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958, and was the first antiestrogen to be discovered. It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested". However, some estrogenic effects in the uterus have been observed, so it is not a pure antiestrogen but is, instead, technically a selective estrogen receptor modulator (SERM). For all intents and purposes, it is a nearly pure antiestrogen, however.

<span class="mw-page-title-main">GTx-758</span> Chemical compound

GTx-758 is a synthetic nonsteroidal estrogen which was under development by GTx, Inc. for the treatment of advanced prostate cancer. As of 2016, it had completed two phase II clinical trials.

<span class="mw-page-title-main">Triphenylchloroethylene</span> Synthetic form of estrogen

Triphenylchloroethylene, or triphenylchlorethylene, also known as chlorotriphenylethylene or as phenylstilbene chloride, is a synthetic nonsteroidal estrogen of the triphenylethylene group that was marketed in the 1940s for the treatment of menopausal symptoms, vaginal atrophy, lactation suppression, and all other estrogen-indicated conditions.

<span class="mw-page-title-main">Droloxifene</span> Chemical compound

Droloxifene, also known as 3-hydroxytamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was developed originally in Germany and later in Japan for the treatment of breast cancer, osteoporosis in men and postmenopausal women, and cardiovascular disorders but was abandoned and never marketed. It reached phase II and phase III clinical trials for these indications before development was discontinued in 2000. The drug was found to be significantly less effective than tamoxifen in the treatment of breast cancer in two phase III clinical trials.

<span class="mw-page-title-main">Nitromifene</span> Chemical compound

Nitromifene (INNTooltip International Nonproprietary Name; also as the citrate salt nitromifene citrate (USANTooltip United States Adopted Name), developmental code names CI-628, CN-5518, CN-55945) is a nonsteroidal selective estrogen receptor modulator (SERM) related to triphenylethylenes like tamoxifen that was never marketed. It is a mixture of (E)- and (Z)-isomers that possess similar antiestrogenic activity. The drug was described in 1966. Along with tamoxifen, nafoxidine, and clomifene, it was one of the earliest SERMs.

A sex-hormonal agent, also known as a sex-hormone receptor modulator, is a type of hormonal agent which specifically modulates the effects of sex hormones and of their biological targets, the sex hormone receptors. The sex hormones include androgens such as testosterone, estrogens such as estradiol, and progestogens such as progesterone. Sex-hormonal agents may be either steroidal or nonsteroidal in chemical structure and may serve to either enhance, inhibit, or have mixed effects on the function of the sex hormone systems.

References

  1. 1 2 3 4 5 6 7 8 9 Sweetman SC, ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. p. 2085. ISBN   978-0-85369-840-1.
  2. 1 2 3 4 5 6 7 8 Meikle AW (24 April 2003). Endocrine Replacement Therapy in Clinical Practice. Springer Science & Business Media. pp. 486–. ISBN   978-1-59259-375-0.
  3. 1 2 3 Ruenitz PC, Toledo MM (August 1981). "Chemical and biochemical characteristics of O-demethylation of chlorotrianisene in the rat". Biochem. Pharmacol. 30 (16): 2203–7. doi:10.1016/0006-2952(81)90088-5. PMID   7295335.
  4. 1 2 3 Jordan VC (1986). Estrogen/antiestrogen Action and Breast Cancer Therapy. Univ of Wisconsin Press. p. 212. ISBN   978-0-299-10480-1.
  5. 1 2 3 4 5 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 263–. ISBN   978-1-4757-2085-3.
  6. 1 2 3 4 5 6 7 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 219–. ISBN   978-3-88763-075-1.
  7. 1 2 3 4 5 6 Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 73–. ISBN   978-94-011-4439-1.
  8. ↑ Cox RL, Crawford ED (December 1995). "Estrogens in the treatment of prostate cancer". The Journal of Urology. 154 (6): 1991–8. doi:10.1016/S0022-5347(01)66670-9. PMID   7500443.
  9. 1 2 3 4 Luniwal A, Jetson R, Erhardt P (2012). "Selective Estrogen Receptor Modulators". In Fischer J, Ganellin CR, Rotella DP (eds.). Analogue-Based Drug Discovery III. pp. 165–185. doi:10.1002/9783527651085.ch7. ISBN   9783527651085.
  10. ↑ Jordan VC, Lieberman ME (September 1984). "Estrogen-stimulated prolactin synthesis in vitro. Classification of agonist, partial agonist, and antagonist actions based on structure". Molecular Pharmacology. 26 (2): 279–85. PMID   6541293.
  11. 1 2 3 Fischer J, Ganellin CR, Rotella DP (15 October 2012). Analogue-based Drug Discovery III. John Wiley & Sons. pp. 5–. ISBN   978-3-527-65110-8.
  12. 1 2 3 4 5 6 7 8 9 Sneader W (23 June 2005). Drug Discovery: A History. John Wiley & Sons. pp. 198–. ISBN   978-0-471-89979-2.
  13. 1 2 Hadden J (9 November 2013). Pharmacology. Springer Science & Business Media. pp. 249–. ISBN   978-1-4615-9406-2.
  14. 1 2 3 4 William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 980–. ISBN   978-0-8155-1856-3.
  15. 1 2 http://www.micromedexsolutions.com/micromedex2/%5B%5D
  16. ↑ Vorherr H (2 December 2012). The Breast: Morphology, Physiology, and Lactation. Elsevier Science. pp. 203–. ISBN   978-0-323-15726-1.
  17. ↑ Schirren C (1961). "Die Sexualhormone". Therapie der Haut- und Geschlechtskrankheiten. pp. 470–549. doi:10.1007/978-3-642-94850-3_6. ISBN   978-3-642-94851-0.
  18. ↑ Kile RL (August 1953). "The treatment of acne with TACE". J Invest Dermatol. 21 (2): 79–81. doi: 10.1038/jid.1953.73 . PMID   13084969.
  19. ↑ Welsh AL (April 1954). "Use of synthetic estrogenic substance chlorotrianisene (TACE) in treatment of acne". AMA Arch Dermatol Syphilol. 69 (4): 418–27. doi:10.1001/archderm.1954.01540160020004. PMID   13147544.
  20. ↑ Dao TL (1975). "Pharmacology and Clinical Utility of Hormones in Hormone Related Neoplasms". In Sartorelli AC, Johns DG (eds.). Antineoplastic and Immunosuppressive Agents. pp. 170–192. doi:10.1007/978-3-642-65806-8_11. ISBN   978-3-642-65806-8.
  21. 1 2 Li JJ (3 April 2009). Triumph of the Heart: The Story of Statins. Oxford University Press, USA. pp. 34–. ISBN   978-0-19-532357-3.
  22. 1 2 3 4 Ghanadian R (6 December 2012). The Endocrinology of Prostate Tumours. Springer Science & Business Media. pp. 70–. ISBN   978-94-011-7256-1.
  23. 1 2 3 Shearer RJ, Hendry WF, Sommerville IF, Fergusson JD (December 1973). "Plasma testosterone: an accurate monitor of hormone treatment in prostatic cancer". Br J Urol. 45 (6): 668–77. doi:10.1111/j.1464-410x.1973.tb12238.x. PMID   4359746.
  24. 1 2 Jordan VC, Mittal S, Gosden B, Koch R, Lieberman ME (September 1985). "Structure-activity relationships of estrogens". Environmental Health Perspectives. 61: 97–110. doi:10.1289/ehp.856197. PMC   1568776 . PMID   3905383.
  25. ↑ Vitamins and Hormones. Academic Press. 18 May 1976. pp. 387–. ISBN   978-0-08-086630-7.
  26. ↑ Khan HN, Blamey RW (August 2003). "Endocrine treatment of physiological gynaecomastia". BMJ. 327 (7410): 301–2. doi:10.1136/bmj.327.7410.301. PMC   1126712 . PMID   12907471.
  27. ↑ Duncan CJ, Kistner RW, Mansell H (October 1956). "Suppression of ovulation by trip-anisyl chloroethylene (TACE)". Obstet Gynecol. 8 (4): 399–407. PMID   13370006.
  28. ↑ Avendano C, Menendez JC (11 June 2015). Medicinal Chemistry of Anticancer Drugs. Elsevier Science. pp. 87–. ISBN   978-0-444-62667-7.
  29. ↑ Manni A (15 January 1999). Endocrinology of Breast Cancer. Springer Science & Business Media. pp. 286–287. ISBN   978-1-59259-699-7.
  30. ↑ Ravina E (11 January 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. pp. 178–. ISBN   978-3-527-32669-3.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.