Chemical compound
Chlorotrianisene
Trade names Tace, Estregur, Anisene, Clorotrisin, Merbentyl, Triagen, others Other names CTA; Trianisylchloroethylene; tri-p -Anisylchloroethylene; TACE; tris(p -Methoxyphenyl)-chloroethylene; NSC-10108
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Multum Consumer Information
Routes of administration
By mouth
[1]
[2]
Drug class
Nonsteroidal estrogen
ATC code
Metabolism Mono-O -
demethylation (
liver
CYP450 )
[3]
[4]
Metabolites
Desmethylchlorotrianisene
[3]
[4]
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
Formula C 23 H 21 Cl O 3
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
Y Key:BFPSDSIWYFKGBC-UHFFFAOYSA-N
Y
(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]
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 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]
References
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b
c
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e
f
g
h
i Sweetman SC, ed. (2009). "Sex hormones and their modulators".
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Endocrine Replacement Therapy in Clinical Practice . Springer Science & Business Media. pp. 486–.
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Estrogen/antiestrogen Action and Breast Cancer Therapy . Univ of Wisconsin Press. p. 212.
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The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies . Springer. pp. 263–.
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Concise Dictionary of Pharmacological Agents: Properties and Synonyms . Springer Science & Business Media. pp. 73–.
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^ Cox RL, Crawford ED (December 1995). "Estrogens in the treatment of prostate cancer". The Journal of Urology . 154 (6): 1991–8.
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^
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c
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doi :
10.1002/9783527651085.ch7 .
ISBN
9783527651085 .
^ 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 .
^
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b
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Analogue-based Drug Discovery III . John Wiley & Sons. pp. 5–.
ISBN
978-3-527-65110-8 .
^
a
b
c
d
e
f
g
h
i Sneader W (23 June 2005).
Drug Discovery: A History . John Wiley & Sons. pp. 198–.
ISBN
978-0-471-89979-2 .
^
a
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Pharmacology . Springer Science & Business Media. pp. 249–.
ISBN
978-1-4615-9406-2 .
^
a
b
c
d William Andrew Publishing (22 October 2013).
Pharmaceutical Manufacturing Encyclopedia, 3rd Edition . Elsevier. pp. 980–.
ISBN
978-0-8155-1856-3 .
^
a
b
http://www.micromedexsolutions.com/micromedex2/ [
permanent dead link ]
^ Vorherr H (2 December 2012).
The Breast: Morphology, Physiology, and Lactation . Elsevier Science. pp. 203–.
ISBN
978-0-323-15726-1 .
^ 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 .
^ 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 .
^ Welsh AL (April 1954). "Use of synthetic estrogenic substance chlorotrianisene (TACE) in treatment of acne". AMA Arch Derm Syphilol . 69 (4): 418–27.
doi :
10.1001/archderm.1954.01540160020004 .
PMID
13147544 .
^ 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 .
^
a
b 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 .
^
a
b
c
d Ghanadian R (6 December 2012).
The Endocrinology of Prostate Tumours . Springer Science & Business Media. pp. 70–.
ISBN
978-94-011-7256-1 .
^
a
b
c 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 .
^
a
b 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 .
^
Vitamins and Hormones . Academic Press. 18 May 1976. pp. 387–.
ISBN
978-0-08-086630-7 .
^ 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 .
^ Duncan CJ, Kistner RW, Mansell H (October 1956).
"Suppression of ovulation by trip-anisyl chloroethylene (TACE)" . Obstet Gynecol . 8 (4): 399–407.
PMID
13370006 .
^ Avendano C, Menendez JC (11 June 2015).
Medicinal Chemistry of Anticancer Drugs . Elsevier Science. pp. 87–.
ISBN
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^ Manni A (15 January 1999).
Endocrinology of Breast Cancer . Springer Science & Business Media. pp. 286–287.
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^ Ravina E (11 January 2011).
The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs . John Wiley & Sons. pp. 178–.
ISBN
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