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| IUPAC_name = (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
| IUPAC_name = (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
| image = File:Ethynerone.svg
| image = File:Ethynerone.svg
| width =
| width =


<!--Clinical data-->
<!--Clinical data-->
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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|last1=Geil|first1=R. G.|last2=Lamar|first2=J. K.|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|year=2009|pages=179–193|issn=0098-4108|doi=10.1080/15287397709529557}}</ref><ref name="JacobsHatfield2012">{{cite journal|last1=Jacobs|first1=A. C.|last2=Hatfield|first2=K. P.|title=History of Chronic Toxicity and Animal Carcinogenicity Studies for Pharmaceuticals|journal=Veterinary Pathology|volume=50|issue=2|year=2012|pages=324–333|issn=0300-9858|doi=10.1177/0300985812450727}}</ref><ref name="Lingeman2012">{{cite book|author=C.H. Lingeman|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]] derivatves 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|author1=V. H. T. James|author2=J. R. Pasqualini|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|last1=Geil|first1=R. G.|last2=Lamar|first2=J. K.|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|year=2009|pages=179–193|issn=0098-4108|doi=10.1080/15287397709529557}}</ref><ref name="JacobsHatfield2012">{{cite journal|last1=Jacobs|first1=A. C.|last2=Hatfield|first2=K. P.|title=History of Chronic Toxicity and Animal Carcinogenicity Studies for Pharmaceuticals|journal=Veterinary Pathology|volume=50|issue=2|year=2012|pages=324–333|issn=0300-9858|doi=10.1177/0300985812450727}}</ref><ref name="Lingeman2012">{{cite book|author=C.H. Lingeman|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]] derivatves 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|author1=V. H. T. James|author2=J. R. Pasqualini|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) [[chloroethynyl norgestrel]] 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) [[chloroethynyl norgestrel]] with mestranol for 4 years at a dosage of 1.05 mg/kg/day cyclically.]]{{Clear}}


==Synthesis==
==Synthesis==
Line 61: Line 61:
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}



{{Progestogenics}}
{{Progestogenics}}

Revision as of 21:32, 28 November 2016

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
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC20H23ClO2
Molar mass330.84842 g/mol 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) 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 chloro-ethynyl 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 derivatves 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) chloroethynyl norgestrel with mestranol for 4 years at a dosage of 1.05 mg/kg/day cyclically.

Synthesis

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

See also

References

  1. ^ J. Elks (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 Benno Clemens Runnebaum; Thomas Rabe; Ludwig Kiesel (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 134–135. ISBN 978-3-642-73790-9.
  3. ^ Egon Diczfalusy; World Health Organization. Acta Endocrinologica: Supplementum. Ejnar Munksgaard. p. 261.
  4. ^ Geil, R. G.; Lamar, J. K. (2009). "FDA studies of estrogen, progestogens, and estrogen/progestogen combinations in the dog and monkey". Journal of Toxicology and Environmental Health. 3 (1–2): 179–193. doi:10.1080/15287397709529557. ISSN 0098-4108.
  5. ^ Jacobs, A. C.; Hatfield, K. P. (2012). "History of Chronic Toxicity and Animal Carcinogenicity Studies for Pharmaceuticals". Veterinary Pathology. 50 (2): 324–333. doi:10.1177/0300985812450727. ISSN 0300-9858.
  6. ^ a b c d C.H. Lingeman (6 December 2012). Carcinogenic Hormones. Springer Science & Business Media. pp. 149–. ISBN 978-3-642-81267-5.
  7. ^ a b V. H. T. James; J. R. Pasqualini (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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