Ethamoxytriphetol

Last updated
Ethamoxytriphetol
Ethamoxytriphetol.svg
Clinical data
Other namesMER-25; NSC-19857
Routes of
administration
By mouth
Identifiers
  • 1-[4-[2-(diethylamino)ethoxy]phenyl]-2-(4-methoxyphenyl)-1-phenylethanol
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C27H33NO3
Molar mass 419.565 g·mol−1
3D model (JSmol)
  • CCN(CC)CCOC1=CC=C(C=C1)C(CC2=CC=C(C=C2)OC)(C3=CC=CC=C3)O
  • InChI=1S/C27H33NO3/c1-4-28(5-2)19-20-31-26-17-13-24(14-18-26)27(29,23-9-7-6-8-10-23)21-22-11-15-25(30-3)16-12-22/h6-18,29H,4-5,19-21H2,1-3H3
  • Key:KDYQVUUCWUPJGE-UHFFFAOYSA-N

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]

Comparison of early clinical experience with antiestrogens for advanced breast cancer
AntiestrogenDosageYear(s)Response rateAdverse effects
Ethamoxytriphetol500–4,500 mg/day196025% Acute psychotic episodes
Clomifene 100–300 mg/day1964–197434%Risks of cataracts
Nafoxidine 180–240 mg/day197631% Cataracts, ichthyosis, photophobia
Tamoxifen 20–40 mg/day1971–197331%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]

See also

Related Research Articles

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

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<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">Toremifene</span> Chemical compound

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<span class="mw-page-title-main">V. Craig Jordan</span> American-British pharmacologist (1947–2024)

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.

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

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.

<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">Triphenylethylene</span> Chemical compound

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<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">Dianol</span> Chemical compound

Dianol is a synthetic, nonsteroidal estrogen that was never marketed. It is a dimer and impurity of anol, and was, along with hexestrol, involved in erroneous findings of highly potent estrogenic activity with anol. Although a potent estrogen, it requires a dose of 100 μg to show activity, whereas hexestrol shows activity with a mere dose of 0.2 μg.

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

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).

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

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

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<span class="mw-page-title-main">ICI-164384</span> Chemical compound

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

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

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<span class="mw-page-title-main">D-15414</span> Chemical compound

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<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.

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