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'''Ethynerone''' ([[International Nonproprietary Name|INN]], [[United States Adopted Name|USAN]]), also known as '''17α-(2-chloroethynyl)estra-4,9-dien-17β-ol-3-one''', is a [[steroid]]al [[progestin]] of the [[19-nortestosterone]] group that was first reported in 1961 but was never marketed.<ref name="Elks2014">{{cite book | vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA521|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=521–}}</ref> Under the developmental code name '''MK-665''', it was studied in [[combination drug|combination]] with [[mestranol]] as an [[combined oral contraceptive pill|oral contraceptive]].<ref name="RunnebaumRabe2012">{{cite book| first1 = Benno Clemens | last1 = Runnebaum | first2 = Thomas | last2 = Rabe | first3 = Ludwig | last3 = Kiesel | name-list-style = vanc |title=Female Contraception: Update and Trends|url=https://books.google.com/books?id=LtT6CAAAQBAJ&pg=PA134|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-73790-9|pages=134–135}}</ref> Development of the drug was discontinued due to concerns surrounding toxicity findings in dogs.<ref name="RunnebaumRabe2012" /> It is a [[chloroethynyl]]ated derivative of [[norethisterone]].<ref name="DiczfalusyOrganization">{{cite book| first1 = Egon | last1 = Diczfalusy | name-list-style = vanc | collaboration = World Health Organization|title=Acta Endocrinologica: Supplementum| year = 1974 |url=https://books.google.com/books?id=0aMnAQAAIAAJ|publisher=Ejnar Munksgaard|page=261| isbn = 9788774940968 }}</ref>
'''Ethynerone''' ([[International Nonproprietary Name|INN]], [[United States Adopted Name|USAN]]), also known as '''17α-(2-chloroethynyl)estra-4,9-dien-17β-ol-3-one''', is a [[steroid]]al [[progestin]] of the [[19-nortestosterone]] group that was first reported in 1961 but was never marketed.<ref name="Elks2014">{{cite book | vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA521|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=521–}}</ref> Under the developmental code name '''MK-665''', it was studied in [[combination drug|combination]] with [[mestranol]] as an [[combined oral contraceptive pill|oral contraceptive]].<ref name="RunnebaumRabe2012">{{cite book| vauthors = Runnebaum BC, Rabe T, Kiesel L |title=Female Contraception: Update and Trends|url=https://books.google.com/books?id=LtT6CAAAQBAJ&pg=PA134|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-73790-9|pages=134–135}}</ref> Development of the drug was discontinued due to concerns surrounding toxicity findings in dogs.<ref name="RunnebaumRabe2012" /> It is a [[chloroethynyl]]ated derivative of [[norethisterone]].<ref name="DiczfalusyOrganization">{{cite book| vauthors = Diczfalusy E | collaboration = World Health Organization|title=Acta Endocrinologica: Supplementum| year = 1974 |url=https://books.google.com/books?id=0aMnAQAAIAAJ|publisher=Ejnar Munksgaard|page=261| isbn = 9788774940968 }}</ref>


In 1966, during its [[clinical development]], ethynerone was found to produce [[mammary gland]] [[tumor]]s in dogs treated with it at very high doses for prolonged periods of time.<ref name="GeilLamar2009">{{cite journal | vauthors = Geil RG, Lamar JK | title = FDA studies of estrogen, progestogens, and estrogen/progestogen combinations in the dog and monkey | journal = Journal of Toxicology and Environmental Health | volume = 3 | issue = 1–2 | pages = 179–93 | date = September 1977 | pmid = 411941 | doi = 10.1080/15287397709529557 }}</ref><ref name="JacobsHatfield2012">{{cite journal | vauthors = Jacobs AC, Hatfield KP | title = History of chronic toxicity and animal carcinogenicity studies for pharmaceuticals | journal = Veterinary Pathology | volume = 50 | issue = 2 | pages = 324–33 | date = March 2013 | pmid = 22700852 | doi = 10.1177/0300985812450727 | s2cid = 22367595 }}</ref><ref name="Lingeman2012">{{cite book| vauthors = Lingeman CH |title=Carcinogenic Hormones|url=https://books.google.com/books?id=lOLnCAAAQBAJ&pg=PA149|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-81267-5|pages=149–}}</ref> Subsequent investigation found that [[17α-hydroxyprogesterone]] derivatives included [[anagestone acetate]], [[chlormadinone acetate]], [[medroxyprogesterone acetate]], and [[megestrol acetate]] produced similar mammary gland tumors, and that their ability to do so correlated directly with their progestogenic actions.<ref name="Lingeman2012" /><ref name="JamesPasqualini2013">{{cite book| vauthors = James VH, Pasqualini JR |title=Hormonal Steroids: Proceedings of the Fifth International Congress on Hormonal Steroids|url=https://books.google.com/books?id=p1AJAwAAQBAJ&pg=PA7|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4831-5895-2|pages=7–8}}</ref> In contrast, the non-halogenated [[19-nortestosterone]] derivatives [[norgestrel]], [[norethisterone]], [[noretynodrel]], and [[etynodiol diacetate]], which are much less potent as progestogens, did not produce such effects at the dosages tested.<ref name="Lingeman2012" /> Clinical development of ethynerone was discontinued, and many of the 17α-hydroxyprogesterone derivatives were withdrawn for the indication of [[hormonal contraception]].<ref name="Lingeman2012" /><ref name="JamesPasqualini2013" /> Research later on revealed species differences between dogs and humans and established that there is no similar risk in humans.<ref name="RunnebaumRabe2012" />
In 1966, during its [[clinical development]], ethynerone was found to produce [[mammary gland]] [[tumor]]s in dogs treated with it at very high doses for prolonged periods of time.<ref name="GeilLamar2009">{{cite journal | vauthors = Geil RG, Lamar JK | title = FDA studies of estrogen, progestogens, and estrogen/progestogen combinations in the dog and monkey | journal = Journal of Toxicology and Environmental Health | volume = 3 | issue = 1–2 | pages = 179–93 | date = September 1977 | pmid = 411941 | doi = 10.1080/15287397709529557 | bibcode = 1977JTEH....3..179G }}</ref><ref name="JacobsHatfield2012">{{cite journal | vauthors = Jacobs AC, Hatfield KP | title = History of chronic toxicity and animal carcinogenicity studies for pharmaceuticals | journal = Veterinary Pathology | volume = 50 | issue = 2 | pages = 324–33 | date = March 2013 | pmid = 22700852 | doi = 10.1177/0300985812450727 | s2cid = 22367595 }}</ref><ref name="Lingeman2012">{{cite book| vauthors = Lingeman CH |title=Carcinogenic Hormones|url=https://books.google.com/books?id=lOLnCAAAQBAJ&pg=PA149|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-81267-5|pages=149–}}</ref> Subsequent investigation found that [[17α-hydroxyprogesterone]] derivatives included [[anagestone acetate]], [[chlormadinone acetate]], [[medroxyprogesterone acetate]], and [[megestrol acetate]] produced similar mammary gland tumors, and that their ability to do so correlated directly with their progestogenic actions.<ref name="Lingeman2012" /><ref name="JamesPasqualini2013">{{cite book| vauthors = James VH, Pasqualini JR |title=Hormonal Steroids: Proceedings of the Fifth International Congress on Hormonal Steroids|url=https://books.google.com/books?id=p1AJAwAAQBAJ&pg=PA7|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4831-5895-2|pages=7–8}}</ref> In contrast, the non-halogenated [[19-nortestosterone]] derivatives [[norgestrel]], [[norethisterone]], [[noretynodrel]], and [[etynodiol diacetate]], which are much less potent as progestogens, did not produce such effects at the dosages tested.<ref name="Lingeman2012" /> Clinical development of ethynerone was discontinued, and many of the 17α-hydroxyprogesterone derivatives were withdrawn for the indication of [[hormonal contraception]].<ref name="Lingeman2012" /><ref name="JamesPasqualini2013" /> Research later on revealed species differences between dogs and humans and established that there is no similar risk in humans.<ref name="RunnebaumRabe2012" />


[[File:Progestin-induced tumors in beagle dogs.png|thumb|left|350px|[[Mammary tumor]]s in [[beagle]] [[dog]]s treated by (left) MK-665 ('''ethynerone''' with [[mestranol]]) and (right) [[chloroethynylnorgestrel]] with mestranol for 4 years at a dosage of 1.05 mg/kg/day cyclically.]]{{Clear}}
[[File:Progestin-induced tumors in beagle dogs.png|thumb|left|350px|[[Mammary tumor]]s in [[beagle]] [[dog]]s treated by (left) MK-665 ('''ethynerone''' with [[mestranol]]) and (right) [[chloroethynylnorgestrel]] with mestranol for 4 years at a dosage of 1.05 mg/kg/day cyclically.]]{{Clear}}

Latest revision as of 12:57, 19 December 2023

Ethynerone
Clinical data
Routes of
administration		Oral
Identifiers
  • (8S,13S,14S,17S)-17-(2-Chloroethynyl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC20H23ClO2
Molar mass330.85 g·mol−1
3D model (JSmol)
  • CC12CCC3=C4CCC(=O)C=C4CCC3C1CCC2(C#CCl)O
  • InChI=1S/C20H23ClO2/c1-19-8-6-16-15-5-3-14(22)12-13(15)2-4-17(16)18(19)7-9-20(19,23)10-11-21/h12,17-18,23H,2-9H2,1H3/t17-,18+,19+,20-/m1/s1
  • Key:KEOBKPHJNAILCW-FUMNGEBKSA-N

Ethynerone (INN, USAN), also known as 17α-(2-chloroethynyl)estra-4,9-dien-17β-ol-3-one, is a steroidal progestin of the 19-nortestosterone group that was first reported in 1961 but was never marketed.[1] Under the developmental code name MK-665, it was studied in combination with mestranol as an oral contraceptive.[2] Development of the drug was discontinued due to concerns surrounding toxicity findings in dogs.[2] It is a chloroethynylated derivative of norethisterone.[3]

In 1966, during its clinical development, ethynerone was found to produce mammary gland tumors in dogs treated with it at very high doses for prolonged periods of time.[4][5][6] Subsequent investigation found that 17α-hydroxyprogesterone derivatives included anagestone acetate, chlormadinone acetate, medroxyprogesterone acetate, and megestrol acetate produced similar mammary gland tumors, and that their ability to do so correlated directly with their progestogenic actions.[6][7] In contrast, the non-halogenated 19-nortestosterone derivatives norgestrel, norethisterone, noretynodrel, and etynodiol diacetate, which are much less potent as progestogens, did not produce such effects at the dosages tested.[6] Clinical development of ethynerone was discontinued, and many of the 17α-hydroxyprogesterone derivatives were withdrawn for the indication of hormonal contraception.[6][7] Research later on revealed species differences between dogs and humans and established that there is no similar risk in humans.[2]

Mammary tumors in beagle dogs treated by (left) MK-665 (ethynerone with mestranol) and (right) chloroethynylnorgestrel with mestranol for 4 years at a dosage of 1.05 mg/kg/day cyclically.

Synthesis

[edit]
Ethynerone synthesis.[8] J. Fried and T. S. Bry U.S. patent 3,096,353 (1963, Merck & Co. Inc).

See also

[edit]

References

[edit]
  1. ^ Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 521–. ISBN 978-1-4757-2085-3.
  2. ^ a b c Runnebaum BC, Rabe T, Kiesel L (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 134–135. ISBN 978-3-642-73790-9.
  3. ^ Diczfalusy E, et al. (World Health Organization) (1974). Acta Endocrinologica: Supplementum. Ejnar Munksgaard. p. 261. ISBN 9788774940968.
  4. ^ Geil RG, Lamar JK (September 1977). "FDA studies of estrogen, progestogens, and estrogen/progestogen combinations in the dog and monkey". Journal of Toxicology and Environmental Health. 3 (1–2): 179–93. Bibcode:1977JTEH....3..179G. doi:10.1080/15287397709529557. PMID 411941.
  5. ^ Jacobs AC, Hatfield KP (March 2013). "History of chronic toxicity and animal carcinogenicity studies for pharmaceuticals". Veterinary Pathology. 50 (2): 324–33. doi:10.1177/0300985812450727. PMID 22700852. S2CID 22367595.
  6. ^ a b c d Lingeman CH (6 December 2012). Carcinogenic Hormones. Springer Science & Business Media. pp. 149–. ISBN 978-3-642-81267-5.
  7. ^ a b James VH, Pasqualini JR (22 October 2013). Hormonal Steroids: Proceedings of the Fifth International Congress on Hormonal Steroids. Elsevier Science. pp. 7–8. ISBN 978-1-4831-5895-2.
  8. ^ p165 Lednicer Mitscher book 1 and p146 (2)
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