Ethamoxytriphetol

Ethamoxytriphetol
Clinical data
Other namesMER-25; NSC-19857
Routes of
administration		By mouth
Identifiers
IUPAC name
  • 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
FormulaC27H33NO3
Molar mass419.565 g·mol−1
3D model (JSmol)
SMILES
  • CCN(CC)CCOC1=CC=C(C=C1)C(CC2=CC=C(C=C2)OC)(C3=CC=CC=C3)O
InChI
  • 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
Antiestrogen Dosage Year(s) Response rate Toxicity
Ethamoxytriphetol 500–4,500 mg/day 1960 25% Acute psychotic episodes
Clomifene 100–300 mg/day 1964–1974 34% Fears of cataracts
Nafoxidine 180–240 mg/day 1976 31% Cataracts, ichthyosis, photophobia
Tamoxifen 20–40 mg/day 1971–1973 31% Transient thrombocytopeniaa
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

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). Tamoxifen: Pioneering Medicine in Breast Cancer. Springer Science & Business Media. pp. 7–. ISBN 978-3-0348-0664-0.
  3. 1 2 3 Jordan VC (1986). 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). 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. ↑ Balthazart J, Ball G (15 November 2012). Brain Aromatase, Estrogens, and Behavior. OUP USA. pp. 161–. ISBN 978-0-19-984119-6.
  6. 1 2 Craig JV, Furr BJ (5 February 2010). 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 / Progrès des recherches pharmaceutiques. Progress in Drug Research. Fortschritte der Arzneimittelforschung. Progrès des Recherches Pharmaceutiques. Vol. 12. pp. 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). The Anticancer Drugs. Oxford University Press. pp. 21–. ISBN 978-0-19-506739-2.
  9. 1 2 3 Manni A (15 January 1999). Endocrinology of Breast Cancer. Springer Science & Business Media. pp. 286–287. ISBN 978-1-59259-699-7.
  10. ↑ Parl FF (1 January 2000). 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 Robert J. Kavlock; George P. Daston (6 December 2012). 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, Anthony; Jordan, V. Craig (2013). "Adjuvant Antihormone Therapy". In Craig, Jordan V. (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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