Etynodiol diacetate

Last updated

Etynodiol diacetate
Ethynodiol diacetate.svg
Clinical data
Trade names Ovulen, Demulen, others
Other namesEthynodiol diacetate; Norethindrol diacetate; 3β-Hydroxynorethisterone 3β,17β-diacetate; [1] 17α-Ethynylestr-4-ene-3β,17β-diyl diacetate; CB-8080; SC-11800
License data
Pregnancy
category
  • Contraindicated
Routes of
administration 		By mouth
Drug class Progestogen; Progestin; Progestogen ester
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only [2] [3]
  • 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
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.005.496 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H32O4
Molar mass 384.516 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, or ethynodiol diacetate, sold under the brand name Ovulen among others, is a progestin medication which is used in birth control pills. [4] [5] [6] The medication is available only in combination with an estrogen. [7] It is taken by mouth. [8]

Contents

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. [9] [10] It has weak androgenic and estrogenic activity and no other important hormonal activity. [11] [12] [13] The medication is a prodrug of norethisterone in the body, with etynodiol occurring as an intermediate. [9] [10] [14]

Etynodiol, a related compound, was discovered in 1954, and etynodiol diacetate was introduced for medical use in 1965. [15] [16] The combination ethynodiol with mestranol (Ovulen) was approved for medical use in the United States in 1966. [17] The combination ethinylestradiol with ethynodiol (Demulen) was approved for medical use in the United States in 1970. [18]

In 2021, the combination with ethinylestradiol was the 276th most commonly prescribed medication in the United States, with more than 800,000 prescriptions. [19] [20]

Medical uses

Etynodiol diacetate is used in combination with an estrogen such as ethinylestradiol or mestranol in combined oral contraceptives for women for the prevention of pregnancy. [8]

Side effects

Pharmacology

Norethisterone (3-ketoetynodiol), the active metabolite of etynodiol diacetate. Norethisterone.svg
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. [9] [10] [14] Upon oral administration and during first-pass metabolism in the liver, etynodiol diacetate is rapidly converted by esterases into etynodiol, [14] which is followed by oxygenation of the C3 hydroxyl group to produce norethisterone. [10] In addition to its progestogenic activity, etynodiol diacetate has weak androgenic activity, [11] [12] and, unlike most progestins but similarly to norethisterone and noretynodrel, [21] also has some estrogenic activity. [12] [13]

The pharmacokinetics of etynodiol diacetate have been reviewed. [22]

Relative affinities (%) of norethisterone, metabolites, and prodrugs
CompoundTypea PR Tooltip Progesterone receptor AR Tooltip Androgen receptor ER Tooltip Estrogen receptor GR Tooltip Glucocorticoid receptor MR Tooltip Mineralocorticoid receptor SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid binding globulin
Norethisterone –67–751500–10–3160
5α-Dihydronorethisterone Metabolite252700 ? ? ?
3α,5α-TetrahydronorethisteroneMetabolite100–10 ? ? ?
3α,5β-TetrahydronorethisteroneMetabolite ?00 ? ? ? ?
3β,5α-TetrahydronorethisteroneMetabolite100–80 ? ? ?
Ethinylestradiol Metabolite15–251–31121–300.180
Norethisterone acetate Prodrug205100 ? ?
Norethisterone enanthate Prodrug ? ? ? ? ? ? ?
Noretynodrel Prodrug6020000
Etynodiol Prodrug1011–180 ? ? ?
Etynodiol diacetateProdrug10000 ? ?
Lynestrenol Prodrug11300 ? ?
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PR Tooltip progesterone receptor, metribolone for the AR Tooltip androgen receptor, estradiol for the ER Tooltip estrogen receptor, dexamethasone for the GR Tooltip glucocorticoid receptor, aldosterone for the MR Tooltip mineralocorticoid receptor, dihydrotestosterone for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip Corticosteroid-binding globulin. Footnotes:a = Active or inactive metabolite, prodrug, or neither of norethisterone. Sources: See template.

Chemistry

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] [5] [6] 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. [5] [6] Etynodiol diacetate is the 3β,17β-diacetate ester of etynodiol (17α-ethynylestr-4-ene-3β,17β-diol). [5] [6]

Synthesis

Ethynodiol diacetate synthesis: 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: Ethynodiol diacetate synthesis.svg
Ethynodiol diacetate synthesis: 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:

Chemical syntheses of etynodiol diacetate have been published. [22]

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). [23]

History

Etynodiol was first synthesized in 1954, via reduction of norethisterone, and etynodiol diacetate was introduced for medical use in 1965. [15] [16]

Society and culture

Generic names

Etynodiol diacetate is the generic name of the drug (the INN Tooltip International Nonproprietary Name of its free alcohol form is etynodiol), while ethynodiol diacetate is its USAN Tooltip United States Adopted Name, BAN Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name. [5] [6] [7] It is also known by its former developmental code names CB-8080 and SC-11800. [5] [6] [7]

Brand names

Etynodiol diacetate is or has been marketed under brand names including Conova, Continuin, Demulen, [18] [25] Femulen, Kelnor, [3] [25] Lo-Malmorede, [26] Luteonorm, Luto-Metrodiol, Malmorede, [27] Metrodiol, Ovulen, [17] [25] Soluna, Zovia, [2] and others. [5] [6] [7]

Availability

Etynodiol diacetate is marketed in only a few countries, including the United States, Canada, Argentina, and Oman. [7]

Related Research Articles

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Desogestrel</span> Medication

Desogestrel is a progestin medication which is used in birth control pills for women. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Drospirenone</span> Medication drug

Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others. The medication is an analog of the drug spironolactone. Drospirenone is taken by mouth.

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

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

<span class="mw-page-title-main">Norelgestromin</span> Pharmaceutical drug

Norelgestromin, or norelgestromine, sold under the brand names Evra and Ortho Evra among others, is a progestin medication which is used as a method of birth control for women. The medication is available in combination with an estrogen and is not available alone. It is used as a patch that is applied to the skin.

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

Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.

<span class="mw-page-title-main">Norgestrel</span> Progestin medication used for birth control

Norgestrel is a progestin which is used in birth control pills sold under the brand name Ovral in combination with the estrogen ethinylestradiol and Opill by itself. It is also used in menopausal hormone therapy. It is taken by mouth.

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

Etynodiol, or ethynodiol, is a steroidal progestin of the 19-nortestosterone group which was never marketed. A diacylated derivative, etynodiol diacetate, is used as a hormonal contraceptive. Etynodiol is sometimes used as a synonym for etynodiol diacetate.

<span class="mw-page-title-main">Norethisterone</span> Progestin medication

Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

<span class="mw-page-title-main">Gestodene</span> Progestin medication

Gestodene, sold under the brand names Femodene and Minulet among others, is a progestin medication which is used in birth control pills for women. It is also used in menopausal hormone therapy. The medication is available almost exclusively in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Lynestrenol</span> Androgen and anabolic steroid

Lynestrenol, sold under the brand names Exluton and Ministat among others, is a progestin medication which is used in birth control pills and in the treatment of gynecological disorders. The medication is available both alone and in combination with an estrogen. It is taken by mouth.

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

Ethisterone, also known as ethinyltestosterone, pregneninolone, and anhydrohydroxyprogesterone and formerly sold under the brand names Proluton C and Pranone among others, is a progestin medication which was used in the treatment of gynecological disorders but is now no longer available. It was used alone and was not formulated in combination with an estrogen. The medication is taken by mouth.

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

Norethisterone enanthate (NETE), also known as norethindrone enanthate, is a form of hormonal birth control which is used to prevent pregnancy in women. It is used both as a form of progestogen-only injectable birth control and in combined injectable birth control formulations. It may be used following childbirth, miscarriage, or abortion. The failure rate per year in preventing pregnancy for the progestogen-only formulation is 2 per 100 women. Each dose of this form lasts two months with only up to two doses typically recommended.

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

Noretynodrel, or norethynodrel, sold under the brand name Enovid among others, is a progestin medication which was previously used in birth control pills and in the treatment of gynecological disorders but is now no longer marketed. It was available both alone and in combination with an estrogen. The medication is taken by mouth.

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

Quingestanol acetate, sold under the brand names Demovis and Pilomin among others, is a progestin medication which was used in birth control pills but is no longer marketed. It is taken by mouth.

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

Ethynerone, 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. Under the developmental code name MK-665, it was studied in combination with mestranol as an oral contraceptive. Development of the drug was discontinued due to concerns surrounding toxicity findings in dogs. It is a chloroethynylated derivative of norethisterone.

<span class="mw-page-title-main">Progestogen ester</span> Drug class

A progestogen ester is an ester of a progestogen or progestin. The prototypical progestogen is progesterone, an endogenous sex hormone. Esterification is frequently employed to improve the pharmacokinetics of steroids, including oral bioavailability, lipophilicity, and elimination half-life. In addition, with intramuscular injection, steroid esters are often absorbed more slowly into the body, allowing for less frequent administration. Many steroid esters function as prodrugs.

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

Ethinylandrostenediol, also known as 17α-ethynyl-5-androstenediol, is a synthetic estrogen, progestogen, and androgen which was never marketed. It is the C17α ethynyl derivative of the androgen precursor and prohormone 5-androstenediol.

References

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  27. ↑ "Malmorede". Archived from the original on 1 October 2023. Retrieved 20 January 2024.
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