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Other names | MER-25; NSC-19857 |
Routes of administration | By mouth |
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Chemical and physical data | |
Formula | C27H33NO3 |
Molar mass | 419.565 g·mol−1 |
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Ethamoxytriphetol (developmental code name MER-25) is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. [1] MER-25 was first reported in 1958, and was the first antiestrogen to be discovered. [2] [3] [4] It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested". [1] [2] However, some estrogenic effects in the uterus have been observed, [2] so it is not a pure antiestrogen (that is, a silent antagonist of the estrogen receptor (ER)) but is, instead, technically a selective estrogen receptor modulator (SERM). [5] For all intents and purposes, it is a nearly pure antiestrogen, however. [6]
MER-25 produces antifertility effects in animals, and garnered interest as a potential hormonal contraceptive. [3] [4] However, clinical development was discontinued due to its low potency and the incidence of unacceptable central nervous system side effects, [3] [4] [7] including hallucinations and psychotic episodes, with higher doses. [8] [9] Undesirable gastrointestinal side effects were also described. [7] Prior to being discontinued, the drug was also administered by Roy Hertz to three patients with metastatic breast cancer and was found to provide relief from bone pain, presumably due to dissolution of bone metastases. [10] [8] This was the first such study of its kind of antiestrogen therapy for the treatment of breast cancer, and it led to the development of tamoxifen for this indication a decade later. [8] The drug was also evaluated for the purpose of ovulation induction and as a treatment of chronic mastitis and endometrial cancer before clinical development was stopped. [9]
MER-25, a simple triphenylethanol derivative, [6] [4] is closely related structurally to the triphenylethylene (TPE) group of SERMs, which includes clomifene and tamoxifen. [2] The drug, a derivative of the cholesterol-lowering agent triparanol (MER-29) (which itself was derived from the estrogen chlorotrianisene (also known as TACE)), [9] [11] was originally being studied in animals at Merrell Dow as a treatment for coronary artery disease. [4] Its antiestrogenic properties were discovered serendipitously when Leonard Lerner, a research endocrinologist at the company who was employed to study nonsteroidal estrogen pharmacology, noted the structural similarity of MER-25 to estrogenic TPE derivatives and decided to test the compound for estrogenicity. [4] Instead of the expected estrogenic effects however, Lerner found that MER-25 blocked the effects of estrogens. [4] Lerner subsequently went on to be involved in the discovery of clomifene, the first potently antiestrogenic TPE derivative to be characterized. [4] The structure of clomifene is similar to that of its predecessor, MER-25. [4] [7] Clomifene is about 10-fold more potent as an antiestrogen than MER-25. [7]
The affinity of ethamoxytriphetol for the rat ER is approximately 0.06% relative to estradiol. [12] [13] For comparison, the affinities of tamoxifen and afimoxifene (4-hydroxytamoxifen) for the rat ER relative to estradiol were 1% and 252%, respectively. [12] [13]
Antiestrogen | Dosage | Year(s) | Response rate | Adverse effects |
---|---|---|---|---|
Ethamoxytriphetol | 500–4,500 mg/day | 1960 | 25% | Acute psychotic episodes |
Clomifene | 100–300 mg/day | 1964–1974 | 34% | Risks of cataracts |
Nafoxidine | 180–240 mg/day | 1976 | 31% | Cataracts, ichthyosis, photophobia |
Tamoxifen | 20–40 mg/day | 1971–1973 | 31% | Transient thrombocytopenia a |
Footnotes:a = "The particular advantage of this drug is the low incidence of troublesome side effects (25)." "Side effects were usually trivial (26)." Sources: [14] [15] |
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.
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.
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.
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.
Virgil Craig Jordan,, was an American and British scientist specializing in drugs for breast cancer treatment and prevention. He was Professor of Breast Medical Oncology, and Professor of Molecular and Cellular Oncology at the University of Texas MD Anderson Cancer Center, Houston, Texas. Previously, he was Scientific Director and Vice Chairman of Oncology at the Lombardi Comprehensive Cancer Center of Georgetown University. Jordan was the first to discover the breast cancer prevention properties of tamoxifen and the scientific principles for adjuvant therapy with antihormones. His later work branched out into the prevention of multiple diseases in women with the discovery of the drug group, selective estrogen receptor modulator (SERMs). He later worked on developing a new Hormone Replacement Therapy (HRT) for post-menopausal women that prevents breast cancer and does not increase the risk of breast cancer.
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.
Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production. Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens. Antiestrogens are commonly used to stop steroid hormones, estrogen, from binding to the estrogen receptors leading to the decrease of estrogen levels. Decreased levels of estrogen can lead to complications in sexual development.
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.
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.
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.
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.
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Etacstil is an orally active, nonsteroidal, combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) that was developed for the treatment of estrogen receptor-positive breast cancer. It was shown to overcome antiestrogen resistance in breast cancer by altering the shape of the estrogen receptor, thus exhibiting SERD properties. Etacstil is a tamoxifen derivative and one of the first drugs to overcome tamoxifen-resistance. It is the predecessor of GW-7604, of which etacstil is a prodrug. This is analogous to the case of tamoxifen being a prodrug of afimoxifene (4-hydroxytamoxifen).
Endoxifen, also known as 4-hydroxy-N-desmethyltamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group as well as a protein kinase C (PKC) inhibitor. It is under development for the treatment of estrogen receptor-positive breast cancer and for the treatment of mania in bipolar disorder. It is taken by mouth.
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.
ICI-164384, also known as N-n-butyl-N-methyl-11-(3,17β-dihydroxyestra-1,3,5 -trien-7α-yl)undecanamide, is a steroidal antiestrogen and a synthetic derivative of estradiol which is closely related to fulvestrant and was never marketed. It is a silent antagonist of the estrogen receptor (ER) with no intrinsic estrogenic activity and hence is a pure antiestrogen, unlike selective estrogen receptor modulators (SERMs) like tamoxifen. The drug was under development by AstraZeneca for the treatment of breast cancer but was discontinued in favor of fulvestrant, which is very similar to ICI-164384 but is more potent in comparison.
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Zindoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) that was under development in the 1980s and early 1990s for the treatment of breast cancer but was not marketed. It showed estrogenic-like activity in preclinical studies and failed to demonstrate effectiveness as a treatment for breast cancer in clinical trials. Zindoxifene was the lead compound of the distinct 2-phenylindole class of SERMs, and the marketed SERM bazedoxifene was derived from the major active metabolite of zindoxifene, D-15414. Zindoxifene was first described in 1984.
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