Anagestone acetate

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Anagestone acetate
Anagestone acetate.svg
Clinical data
Trade names Anatropin, Neo-Novum
Other namesORF-1658; Anapregnone acetate; 3-Deketo-6α-methyl-17α-acetoxyprogesterone; 6α-Methyl-17α-hydroxypregn-4-en-20-one acetate
Routes of
administration 		By mouth
Drug class Progestogen; Progestin; Progestogen ester
Identifiers
  • [(6S,8R,9S,10R,13S,14S,17R)-17-acetyl-6,10,13-trimethyl-1,2,3,6,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard 100.019.578 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H36O3
Molar mass 372.549 g·mol−1
3D model (JSmol)
  • C[C@H]1C[C@@H]2[C@H](CC[C@]3([C@H]2CC[C@@]3(C(=O)C)OC(=O)C)C)[C@@]4(C1=CCCC4)C
  • InChI=1S/C24H36O3/c1-15-14-18-20(22(4)11-7-6-8-19(15)22)9-12-23(5)21(18)10-13-24(23,16(2)25)27-17(3)26/h8,15,18,20-21H,6-7,9-14H2,1-5H3/t15-,18+,20-,21-,22-,23-,24-/m0/s1
  • Key:KDLNOQQQEBKBQM-DICPTYMLSA-N

Anagestone acetate, sold under the brand names Anatropin and Neo-Novum, is a progestin medication which was withdrawn from medical use due to carcinogenicity observed in animal studies. [1] [2] [3]

Contents

Medical uses

Anagestone acetate was used in combination with the estrogen mestranol as a combined birth control pill. [4] [5]

Pharmacology

Based on its chemical structure, namely the lack of a C3 ketone, it is probable that anagestone acetate is a prodrug of medroxyprogesterone acetate (the 3-keto analogue). [6] [7]

Chemistry

Anagestone acetate, also known as 3-deketo-6α-methyl-17α-acetoxyprogesterone or as 6α-methyl-17α-acetoxypregn-4-en-20-one, is a synthetic pregnane steroid and a derivative of progesterone and 17α-hydroxyprogesterone. [1] It is the C17α acetate ester of anagestone, which, in contrast to anagestone acetate, was never marketed. [1] Anagestone acetate is closely related structurally to medroxyprogesterone acetate (6α-methyl-17α-acetoxyprogesterone). [1]

History

Anagestone acetate was introduced in combination with mestranol as a birth control pill in 1968 by Ortho Pharmaceutical. [4] [5] It was withdrawn in 1969. [5] [8]

In 1969, along with a variety of other progestogens including progesterone, chlormadinone acetate, megestrol acetate, medroxyprogesterone acetate, ethynerone, and chloroethynyl norgestrel, anagestone acetate was found to induce the development of mammary gland tumors in Beagle dogs after extensive treatment (2–7 years) with very high doses (10–25 times the recommended human dose), though notably not with 1–2 times the human dosage. [5] [9] [8] In contrast, the non-halogenated 19-nortestosterone derivatives norgestrel, norethisterone, noretynodrel, and etynodiol diacetate were not found to produce such nodules. [8] Because of these findings, anagestone acetate was voluntarily withdrawn from the market by the manufacturer in 1969. [5] [8] [10] The findings also led to the virtual disappearance of most 17α-hydroxyprogesterone derivatives as hormonal contraceptives from the market (though medroxyprogesterone acetate, cyproterone acetate, and chlormadinone acetate have continued to be used). [5] [9] According to Hughes et al., "It is still doubtful how much relevance these findings have for humans as the dog mammary gland seems to be the only one which can be directly maintained by progestogens." [8] [11] Subsequent research revealed species differences between dogs and humans and established that there is no similar risk in humans. [12]

Society and culture

Generic names

Anagestone acetate is the generic name of the drug and its USAN. [1] It is also known by its developmental code name ORF-1658. [1]

Brand names

Anagestone acetate was marketed under the brand names Anatropin and Neo-Novum, the latter in combination with the estrogen mestranol. [1]

Availability

Anagestone acetate was withdrawn from the market and is no longer available. [5] [8] [10]

See also

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">17α-Hydroxyprogesterone</span> Chemical compound

17α-Hydroxyprogesterone (17α-OHP), also known as 17-OH progesterone (17-OHP), or hydroxyprogesterone (OHP), is an endogenous progestogen steroid hormone related to progesterone. It is also a chemical intermediate in the biosynthesis of many other endogenous steroids, including androgens, estrogens, glucocorticoids, and mineralocorticoids, as well as neurosteroids.

<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">Etynodiol diacetate</span> Chemical compound

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. The medication is available only in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Medroxyprogesterone</span> Steroidal progestin drug

Medroxyprogesterone (MP), is a progestin which is not used medically. A derivative, medroxyprogesterone acetate (MPA), is used as a medication in humans, and is far more widely known in comparison. Medroxyprogesterone is sometimes used as a synonym for medroxyprogesterone acetate, and what is almost always being referred to when the term is used is MPA and not medroxyprogesterone.

Combined injectable contraceptives (CICs) are a form of hormonal birth control for women. They consist of monthly injections of combined formulations containing an estrogen and a progestin to prevent pregnancy.

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

Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy, as a component of menopausal hormone therapy, in the treatment of gynecological disorders, and in the treatment of androgen-dependent conditions like enlarged prostate and prostate cancer in men and acne and hirsutism in women. It is available both at a low dose in combination with an estrogen in birth control pills and, in a few countries like France and Japan, at low, moderate, and high doses alone for various indications. It is taken by mouth.

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

Dimethisterone, formerly sold under the brand names Lutagan and Secrosteron among others, is a progestin medication which was used in birth control pills and in the treatment of gynecological disorders but is now no longer available. It was used both alone and in combination with an estrogen. It is taken by mouth.

<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">Hydroxyprogesterone acetate</span> Chemical compound

Hydroxyprogesterone acetate (OHPA), sold under the brand name Prodox, is an orally active progestin related to hydroxyprogesterone caproate (OHPC) which has been used in clinical and veterinary medicine. It has reportedly also been used in birth control pills.

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

Haloprogesterone, sold under the brand name Prohalone, is a progestin medication which was previously marketed by Ayerst but is now no longer available.

<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">Chloroethynylnorgestrel</span> Chemical compound

Chloroethynylnorgestrel is a steroidal progestin of the 19-nortestosterone group related to norgestrel that was investigated as an oral contraceptive in the 1970s but was never marketed.

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

Acetomepregenol (ACM), also known as mepregenol diacetate and sold under the brand name Diamol, is a progestin medication which is used in Russia for the treatment of gynecological conditions and as a method of birth control in combination with an estrogen. It has also been studied in the treatment of threatened abortion. It has been used in veterinary medicine as well. It has been marketed since at least 1981.

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

Flumedroxone acetate, sold under the brand names Demigran and Leomigran, is a progestin medication which is or has been used as an antimigraine agent. It is taken by mouth.

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

Chlormadinone caproate (CMC) is a progestin and a progestogen ester which was studied for potential use in combined injectable contraceptives but was never marketed. It was assessed in combination with estradiol valerate at doses of 80 mg and 3 mg, respectively. In addition to chlormadinone acetate (CMA), analogues of CMC include gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone caproate, megestrol caproate, and methenmadinone caproate.

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

Medroxyprogesterone caproate (MPC) is a progestin and a progestogen ester which was synthesized in 1958 but was never marketed. It has been confused with hydroxyprogesterone caproate (OHPC) and medroxyprogesterone acetate (MPA) in a number of publications. In addition to MPA and OHPC, analogues of MPC include chlormadinone caproate, gestonorone caproate, megestrol caproate, and methenmadinone caproate.

<span class="mw-page-title-main">6α-Methylprogesterone</span> Chemical compound

6α-Methylprogesterone (6α-MP) is a progestin which was never marketed. It has 150% of the progestogenic potency of progesterone. In addition, and in contrast to progesterone, 6α-MP has weak androgenic, antiandrogenic, and synandrogenic actions. 6α-MP is structurally related to medroxyprogesterone acetate and megestrol acetate, which possess androgenic and/or antiandrogenic activity to varying degrees similarly. MPA is more androgenic than 6α-MP and MGA.

References

  1. 1 2 3 4 5 6 7 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 85–. ISBN   978-1-4757-2085-3.
  2. ↑ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 322–. ISBN   978-0-8155-1856-3.
  3. ↑ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1987). IV. OESTROGEN-PROGESTIN COMBINATIONS. International Agency for Research on Cancer. Retrieved 24 June 2022.
  4. 1 2 Schreiner WE (6 December 2012). "The Ovary". In Labhart A (ed.). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 571–. ISBN   978-3-642-96158-8.
  5. 1 2 3 4 5 6 7 Streffer C, Bolt H, Follesdal D, Hall P, Hengstler JG, Jacob P, et al. (11 November 2013). "Interspecies Compeition". Low Dose Exposures in the Environment: Dose-Effect Relations and Risk Evaluation. Springer Science & Business Media. pp. 135–. ISBN   978-3-662-08422-9.
  6. ↑ Fraser IS (1998). Estrogens and Progestogens in Clinical Practice. Churchill Livingstone. p. 281. ISBN   978-0-443-04706-0. Progestational activity depends on the presence of a 3-keto group in ring A of the steroid skeleton. Most of the progestogens used today do indeed carry such a group in their original molecules. However, the 3-keto group is initially missing in the case of desogestrel and norgestimate. They are prodrugs which undergo metabolic conversion to active 3-keto derivatives in the body.
  7. ↑ McRobb L, Handelsman DJ, Kazlauskas R, Wilkinson S, McLeod MD, Heather AK (May 2008). "Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay". The Journal of Steroid Biochemistry and Molecular Biology. 110 (1–2): 39–47. doi:10.1016/j.jsbmb.2007.10.008. PMID   18395441. S2CID   5612000. Prodrugs (lack 3-keto): Ethylestrenol, Lynestrenol, Ethynodiol, Allylestrenol, Norgestimate
  8. 1 2 3 4 5 6 Casey HW, Giles RC, Kwapien RP (1979). "Mammary Neoplasia in Animals: Pathologic Aspects and the Effects of Contraceptive Steroids". Carcinogenic Hormones. Vol. 66. pp. 129–160 (149). doi:10.1007/978-3-642-81267-5_4. ISBN   978-3-540-08995-7. PMID   107546.{{cite book}}: |journal= ignored (help)
  9. 1 2 Diczfalusy E (July 1979). "Gregory Pincus and steroidal contraception: a new departure in the history of mankind". Journal of Steroid Biochemistry. 11 (1A): 3–11. doi:10.1016/0022-4731(79)90271-1. PMID   385985.
  10. 1 2 Consolidated List of Products Whose Consumption And/or Sale Have Been Banned, Withdrawn, Severely Restricted Or Not Approved by Governments. United Nations Publications. 1983. pp. 25–. ISBN   978-92-1-130230-1.
  11. ↑ Gräf KJ, Brotherton J, Neumann F (27 November 2013). "The Clinical Uses of Antiandrogens". In Hughes A, Hasan SH, Oertel GW, Voss HE, Bahner F, Neumann F, et al. (eds.). Androgens II and Antiandrogens / Androgene II und Antiandrogene. Springer Science & Business Media. pp. 531–. ISBN   978-3-642-80859-3.
  12. ↑ Runnebaum BC, Rabe T, Kiesel L (6 December 2012). "Development of Progestogens". Female Contraception: Update and Trends. Springer Science & Business Media. pp. 134–135. ISBN   978-3-642-73790-9.
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