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 (born 1947)

Virgil Craig Jordan,, is a scientist with American and British citizenship specializing in drugs for breast cancer treatment and prevention. Currently, he is 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. More recently his work has branched out into the prevention of multiple diseases in women with the discovery of the drug group, selective estrogen receptor modulator (SERMs). Currently, he plans to develop 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. Antiandrogens are sex hormone antagonists which are able to lower the production and the effects that testosterone can have on female bodies.

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

Nafoxidine or nafoxidine hydrochloride (USAN) 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">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

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<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">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 (INN; also as the citrate salt nitromifene citrate (USAN), 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.

References

  1. 1 2 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.
  2. 1 2 3 4 Maximov PY, McDaniel RE, Jordan VC (23 July 2013). "Discovery and Pharmacology of Nonsteroidal Estrogens and Antiestrogens". Tamoxifen: Pioneering Medicine in Breast Cancer. Springer Science & Business Media. pp. 7–. ISBN   978-3-0348-0664-0.
  3. 1 2 3 Jordan VC, Koch R, Lieberman ME (1986). "Structure-Activity Relationships of Nonsteroidal Estrogens and Antiestrogens". In Jordan VC (ed.). Estrogen/antiestrogen Action and Breast Cancer Therapy. Univ of Wisconsin Press. pp. 28, 154. ISBN   978-0-299-10480-1.
  4. 1 2 3 4 5 6 7 8 9 Jordan VC (27 May 2013). "A Century of Deciphering the Control Mechanisms of Estrogen Action in Breast Cancer: The Origins of Targeted Therapy and Chemoprevention". In Jordan VC (ed.). Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health: Progress and Promise. World Scientific. pp. 7, 112. ISBN   978-1-84816-959-3.
  5. ↑ Clemens LG (15 November 2012). "The Aromatization Hypothesis 1970-1990". In Balthazart J, Ball G (eds.). Brain Aromatase, Estrogens, and Behavior. OUP USA. pp. 161–. ISBN   978-0-19-984119-6.
  6. 1 2 Wakeling AE (5 February 2010). "Pure Antiestrogen". In Jorden VC, Furr BJ (eds.). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 4, 161. ISBN   978-1-59259-152-7.
  7. 1 2 3 4 Harper MJ (1968). "Pharmacological Control of Reproduction in Women". Progress in Drug Research. Fortschritte der Arzneimittelforschung. Progres des Recherches Pharmaceutiques. 12: 47–136. doi:10.1007/978-3-0348-7065-8_2. ISBN   978-3-0348-7067-2. PMID   4892528.
  8. 1 2 3 Pratt WB (1994). "Determinants of Drug Responsiveness". The Anticancer Drugs. Oxford University Press. pp. 21–. ISBN   978-0-19-506739-2.
  9. 1 2 3 Gradishar WJ, Jordon VC (15 January 1999). "Pharmacology and Use of Antiestrogens in Treatment and Chemoprevention of Breast Cancer". In Manni A (ed.). Endocrinology of Breast Cancer. Springer Science & Business Media. pp. 286–287. ISBN   978-1-59259-699-7.
  10. ↑ Parl FF (1 January 2000). "Introduction". Estrogens, Estrogen Receptor, and Breast Cancer. IOS Press. pp. 13–. ISBN   978-0-9673355-4-4.
  11. ↑ 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.
  12. 1 2 Chander SK, Sahota SS, Evans TR, Luqmani YA (December 1993). "The biological evaluation of novel antioestrogens for the treatment of breast cancer". Crit Rev Oncol Hematol. 15 (3): 243–69. doi:10.1016/1040-8428(93)90044-5. PMID   8142059.
  13. 1 2 Kelce WR, Grary Jr LE (6 December 2012). "Endocrine Disruptors: Effects on Sex Steroid Hormone Receptors and Sex Development". In Kavlock RJ, Daston GP (eds.). Drug Toxicity in Embryonic Development II: Advances in Understanding Mechanisms of Birth Defects: Mechanistics Understanding of Human Development Toxicants. Springer Science & Business Media. pp. 437–. ISBN   978-3-642-60447-8.
  14. ↑ Jensen EV, Jordan VC (June 2003). "The estrogen receptor: a model for molecular medicine". Clin. Cancer Res. 9 (6): 1980–9. PMID   12796359.
  15. ↑ Howell A, Jordan VC (2013). "Adjuvant Antihormone Therapy". In Craig JV (ed.). Estrogen Action, Selective Estrogen Receptor Modulators And Women's Health: Progress And Promise. World Scientific. pp. 229–254. doi:10.1142/9781848169586_0010. ISBN   978-1-84816-959-3.
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