Etynodiol diacetate

Etynodiol diacetate, or ethynodiol diacetate, sold under the brand names Demulen and Femulen among others, is a progestin medication which is used in birth control pills.[2][3][4] The medication is available only in combination with an estrogen.[5] It is taken by mouth.[6]

Etynodiol diacetate
Clinical data
Trade namesContinuin, Demulen, Femulen, Luteonorm, Luto-Metrodiol, Metrodiol, Ovulen, others
Other namesEthynodiol diacetate; Norethindrol diacetate; 3β-Hydroxynorethisterone 3β,17β-diacetate;[1] 17α-Ethynylestr-4-ene-3β,17β-diyl diacetate; CB-8080; SC-11800
Routes of
administration		By mouth
Drug classProgestogen; Progestin; Progestogen ester
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • [(3S,8R,9S,10R,13S,14S,17R)-17-acetyloxy-17-ethynyl-13-methyl-2,3,6,7,8,9,10,11,12,14,15,16-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] acetate
CAS Number
PubChem CID
PubChem SID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.005.496
Chemical and physical data
FormulaC24H32O4
Molar mass384.516 g·mol−1
3D model (JSmol)
  • O=C(O[C@@H]4/C=C3\[C@@H]([C@H]2CC[C@]1([C@@H](CC[C@]1(C#C)OC(=O)C)[C@@H]2CC3)C)CC4)C
  • InChI=1S/C24H32O4/c1-5-24(28-16(3)26)13-11-22-21-8-6-17-14-18(27-15(2)25)7-9-19(17)20(21)10-12-23(22,24)4/h1,14,18-22H,6-13H2,2-4H3/t18-,19-,20+,21+,22-,23-,24-/m0/s1
  • Key:ONKUMRGIYFNPJW-KIEAKMPYSA-N

Etynodiol diacetate is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[7][8] It has weak androgenic and estrogenic activity and no other important hormonal activity.[9][10][11] The medication is a prodrug of norethisterone in the body, with etynodiol occurring as an intermediate.[7][8][12]

Etynodiol, a related compound, was discovered in 1954, and etynodiol diacetate was introduced for medical use in 1965.[13][14] The medication remains available today only in the United States, Canada, and a few other countries.[4][5]

Medical uses

Etynodiol diacetate is used in combination with an estrogen such as ethinylestradiol or mestranol in combined oral contraceptives for women.[6]

Side effects
See also: Norethisterone § Side effects, and Progestin § Side effects

Pharmacology
Norethisterone (3-ketoetynodiol), the active metabolite of etynodiol diacetate.

Etynodiol diacetate is virtually inactive in terms of affinity for the progesterone and androgen receptors and acts as a rapidly converted prodrug of norethisterone, with etynodiol occurring as an intermediate.[7][8][12] Upon oral administration and during first-pass metabolism in the liver, etynodiol diacetate is rapidly converted by esterases into etynodiol,[12] which is followed by oxygenation of the C3 hydroxyl group to produce norethisterone.[8] In addition to its progestogenic activity, etynodiol diacetate has weak androgenic activity,[9][10] and, unlike most progestins but similarly to norethisterone and noretynodrel,[15] also has some estrogenic activity.[10][11]

The pharmacokinetics of etynodiol diacetate have been reviewed.[16]

Relative affinities (%) of norethisterone, metabolites, and prodrugs
CompoundTypeaPRTooltip Progesterone receptorARTooltip Androgen receptorERTooltip Estrogen receptorGRTooltip Glucocorticoid receptorMRTooltip Mineralocorticoid receptorSHBGTooltip Sex hormone-binding globulinCBGTooltip Corticosteroid binding globulin
Norethisterone–67–751500–10–3160
5α-DihydronorethisteroneMetabolite252700 ? ? ?
3α,5α-TetrahydronorethisteroneMetabolite100–10 ? ? ?
3α,5β-TetrahydronorethisteroneMetabolite ?00 ? ? ? ?
3β,5α-TetrahydronorethisteroneMetabolite100–80 ? ? ?
EthinylestradiolMetabolite15–251–31121–300.180
Norethisterone acetateProdrug205100 ? ?
Norethisterone enanthateProdrug ? ? ? ? ? ? ?
NoretynodrelProdrug6020000
EtynodiolProdrug1011–180 ? ? ?
Etynodiol diacetateProdrug10000 ? ?
LynestrenolProdrug11300 ? ?
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PRTooltip progesterone receptor, metribolone for the ARTooltip androgen receptor, estradiol for the ERTooltip estrogen receptor, dexamethasone for the GRTooltip glucocorticoid receptor, aldosterone for the MRTooltip mineralocorticoid receptor, dihydrotestosterone for SHBGTooltip sex hormone-binding globulin, and cortisol for CBGTooltip Corticosteroid-binding globulin. Footnotes: a = Active or inactive metabolite, prodrug, or neither of norethisterone. Sources: See template.

Chemistry
See also: List of progestogens, Progestogen ester, and List of progestogen esters

Etynodiol diacetate, also known as 3β-hydroxy-17α-ethynyl-19-nortestosterone 3β,17β-diaceate, 3β-hydroxynorethisterone 3β,17β-diacetate, or 17α-ethynylestr-4-ene-3β,17β-diol 3β,17β-diacetate, is a synthetic estrane steroid and a derivative of testosterone.[1][3][4] It is specifically a derivative of 19-nortestosterone and 17α-ethynyltestosterone, or of norethisterone (17α-ethynyl-19-nortestosterone), in which the C3 ketone group has been dehydrogenated into a C3β hydroxyl group and acetate esters have been attached at the C3β and C17β positions.[3][4] Etynodiol diacetate is the 3β,17β-diacetate ester of etynodiol (17α-ethynylestr-4-ene-3β,17β-diol).[3][4]

Synthesis
Ethynodiol diacetate synthesis:[17] F. B. Colton, U.S. Patent 2,843,609 (1958 to Searle). Prepn of the 3-acetate, 17-acetate, and diacetate: P. D. Klimstra, U.S. Patent 3,176,013 (1965 to Searle); see also:[18]

Chemical syntheses of etynodiol diacetate have been published.[16]

Reduction of norethisterone (1) affords the 3,17-diol. The 3β-hydroxy compound is the desired product; since reactions at C3 do not show nearly the stereoselectivity as those at C17 by virtue of the relative lack of stereo-directing proximate substituents, the formation of the desired isomer is engendered by use of a bulky reducing agent, lithium tri-tert-butoxyaluminum hydride. Acetylation of the 3β,17β-diol affords etynodiol diacetate (3).[17]

History

Etynodiol was first synthesized in 1954, via reduction of norethisterone, and etynodiol diacetate was introduced for medical use in 1965.[13][14]

Society and culture

Generic names

Etynodiol diacetate is the generic name of the drug (the INNTooltip International Nonproprietary Name of its free alcohol form is etynodiol), while ethynodiol diacetate is its USANTooltip United States Adopted Name, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name.[3][4][5] It is also known by its former developmental code names CB-8080 and SC-11800.[3][4][5]

Brand names

Etynodiol diacetate is or has been marketed under brand names including Conova, Continuin, Demulen, Femulen, Kelnor, Luteonorm, Luto-Metrodiol, Metrodiol, Ovulen, Soluna, Zovia, and others.[3][4][5]

Availability

Etynodiol diacetate remains marketed in only a few countries, including the United States, Canada, Argentina, and Oman.[5]

References
  1. Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (December 2003). "Classification and pharmacology of progestins". Maturitas. 46 (Suppl 1): S7–S16. doi:10.1016/j.maturitas.2003.09.014. PMID 14670641.
  2. Shoupe D, Haseltine FP (6 December 2012). Contraception. Springer Science & Business Media. pp. 21–. ISBN 978-1-4612-2730-4.
  3. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 522–. ISBN 978-1-4757-2085-3.
  4. Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 422. ISBN 978-3-88763-075-1. Retrieved 30 May 2012.
  5. "Etynodiol". Drugs.com. Archived from the original on 2018-02-05. Retrieved 2018-02-04.
  6. Blum RW (22 October 2013). Adolescent Health Care: Clinical Issues. Elsevier Science. pp. 216–. ISBN 978-1-4832-7738-7.
  7. Hammerstein J (December 1990). "Prodrugs: advantage or disadvantage?". American Journal of Obstetrics and Gynecology. 163 (6 Pt 2): 2198–2203. doi:10.1016/0002-9378(90)90561-K. PMID 2256526.
  8. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 146–. ISBN 978-92-832-1291-1.
  9. Tashjian AH, Armstrong EJ (21 July 2011). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Lippincott Williams & Wilkins. pp. 523–. ISBN 978-1-4511-1805-6.
  10. Becker KL (24 April 2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. p. 1004. ISBN 978-0-7817-1750-2. Retrieved 30 May 2012.
  11. Goroll AH, Mulley AG (27 January 2009). Primary Care Medicine: Office Evaluation and Management of the Adult Patient. Lippincott Williams & Wilkins. p. 876. ISBN 978-0-7817-7513-7. Retrieved 30 May 2012.
  12. Stanczyk FZ (September 2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Reviews in Endocrine & Metabolic Disorders. 3 (3): 211–224. doi:10.1023/A:1020072325818. PMID 12215716. S2CID 27018468.
  13. Petrow V (1971). "Antifertility agents". Progress in Medicinal Chemistry. 8 (2): 171–229. doi:10.1016/s0079-6468(08)70130-9. PMID 4947236.
  14. William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1516–. ISBN 978-0-8155-1856-3.
  15. Runnebaum BC, Rabe T, Kiesel L (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 36–. ISBN 978-3-642-73790-9.
  16. Konstitution J (27 November 2013). "Eigenschaften der Gestagene". Handbuch der Experimentellen Pharmakologie. Cham: Springer-Verlag. pp. 14–15, 286. ISBN 978-3-642-99941-3.
  17. Klimstra PD, Colton FB (October 1967). "The synthesis of 3beta-hydroxyestr-4-en-17-one and 3beta-hydroxyandrost-4-en-17-one". Steroids. 10 (4): 411–424. doi:10.1016/0039-128X(67)90119-5. PMID 6064262.
  18. Sondheimer F, Klibansky Y (1959). "Synthesis of 3β-hydroxy analogues of steroidal hormones, a biologically active class of compounds". Tetrahedron. 5: 15–26. doi:10.1016/0040-4020(59)80066-1.
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