Chlorotrianisene

Chlorotrianisene

Clinical data
Trade names	Tace, Estregur, Anisene, Clorotrisin, Merbentyl, Triagen, others
Other names	CTA; Trianisylchloroethylene; tri-p-Anisylchloroethylene; TACE; tris(p-Methoxyphenyl)-chloroethylene; NSC-10108
AHFS/Drugs.com	Multum Consumer Information
Routes of administration	By mouth
Drug class	Nonsteroidal estrogen
ATC code	G03CA06 (WHO)
Pharmacokinetic data
Metabolism	Mono-O-demethylation (liver CYP450)
Metabolites	Desmethylchlorotrianisene
Identifiers
IUPAC name 1,1',1''-(2-chloroethene-1,1,2-triyl)tris(4-methoxybenzene); 11-chloro-4,13-dimethoxy-12-(p-methoxyphenyl)stilbene
CAS Number	569-57-3 Y
PubChem CID	11289
IUPHAR/BPS	7146
DrugBank	DB00269 Y
ChemSpider	10815 Y
UNII	6V5034L121
KEGG	D00269 Y
ChEBI	CHEBI:3641 Y
ChEMBL	ChEMBL1200761 Y
CompTox Dashboard (EPA)	DTXSID1021299
ECHA InfoCard	100.008.472
Chemical and physical data
Formula	C23H21ClO3
Molar mass	380.87 g·mol−1
3D model (JSmol)	Interactive image
SMILES COc1ccc(C(Cl)=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
InChI 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
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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. It is taken by mouth.

CTA is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol. 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. CTA itself is inactive and is a prodrug in the body.

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

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. It has been used to suppress lactation in women. CTA has been used in the treatment of acne as well.

Side effects

In men, CTA can produce gynecomastia as a side effect. 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.

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).

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

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. 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. 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.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. As an example, chlorotrianisene produces gynecomastia in men, albeit reportedly to a lesser extent than other estrogens, while clomifene and tamoxifen do not and can be used to treat gynecomastia.

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

Chemistry

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

History

CTA was introduced for medical use in the United States in 1952, and was subsequently introduced for use throughout Europe. It was the first estrogenic compound of the triphenylethylene series to be introduced. 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). The SERMs clomifene and tamoxifen, as well as the antiestrogen ethamoxytriphetol, were derived from CTA via structural modification.

Society and culture

Generic names

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

Brand names

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

Availability

CTA is no longer marketed and hence is no longer available in any country. It was previously used in the United States and Europe.