Demegestone

Last updated
Demegestone
Demegestone.svg
Demegestone 3D ball.png
Clinical data
Trade names Lutionex
Other namesDimegestone; R-2453; RU-2453; 17α-Methyl-δ9-19-norprogesterone; 17α-Methyl-19-norpregna-4,9-diene-3,20-dione
Routes of
administration 		By mouth [1]
Drug class Progestogen; Progestin
ATC code
Pharmacokinetic data
Bioavailability Good [2]
Metabolism Hydroxylation, others [2]
Metabolites • 21-Hydroxydemegestone [2]
• Others [2]
Excretion Urine [2]
Identifiers
  • (8S,13S,14S,17S)-17-acetyl-13,17-dimethyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.030.278 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H28O2
Molar mass 312.453 g·mol−1
3D model (JSmol)
  • CC(=O)[C@]1(CC[C@@H]2[C@@]1(CCC3=C4CCC(=O)C=C4CC[C@@H]23)C)C
  • InChI=1S/C21H28O2/c1-13(22)20(2)11-9-19-18-6-4-14-12-15(23)5-7-16(14)17(18)8-10-21(19,20)3/h12,18-19H,4-11H2,1-3H3/t18-,19+,20-,21+/m1/s1
  • Key:JWAHBTQSSMYISL-MHTWAQMVSA-N

Demegestone, sold under the brand name Lutionex, is a progestin medication which was previously used to treat luteal insufficiency but is now no longer marketed. [3] [4] [5] [6] [7] It is taken by mouth. [2] [1]

Contents

Demegestone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. [6] [2] [8] It has no androgenic activity. [2]

Demegestone was first described in 1966 and was introduced for medical use in France in 1974. [3] [4] It has only been marketed in France, and has since been discontinued in this country. [5] [4]

Medical uses

Demegestone has been used to treat luteal insufficiency. [7] It has also been studied in combination with estrogens, such as moxestrol, as an oral contraceptive and treatment for infertility. [1] [9] [10]

Side effects

Pharmacology

Pharmacodynamics

Demegestone is a progestogen, and hence is an agonist of the progesterone receptor (PR). [6] [8] [2] It is a highly potent progestogen, showing 50 times the potency of progesterone in the Clauberg test. [2] The ovulation-inbhiting dosage of demegestone is 2.5 mg/day, while the endometrial transformation dosage is 100 mg per cycle. [11] The medication is devoid of androgenic activity, [2] and instead has some antiandrogenic activity. [12] Demegestone has low affinity for the glucocorticoid receptor. [13] In a particular bioassay, both demegestone and progesterone showed antiglucocorticoid rather than glucocorticoid activity. [14] The major metabolite of demegestone, a 21-hydroxylated metabolite, is a moderately potent progestogen (4 times the potency of progesterone) and a weak mineralocorticoid (2% of the potency of deoxycorticosterone). [2]

Relative affinities (%) of demegestone
Compound 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
Demegestone2301051–2 ? ?
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PR Tooltip progesterone receptor, testosterone for the AR Tooltip androgen receptor, E2 for the ER Tooltip estrogen receptor, DEXA Tooltip dexamethasone for the GR Tooltip glucocorticoid receptor, aldosterone for the MR Tooltip mineralocorticoid receptor, DHT Tooltip dihydrotestosterone for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip Corticosteroid-binding globulin. Sources: [13] [15] [16] [17]

Pharmacokinetics

Demegestone has good bioavailability. [2] The initial volume of distribution of demegestone is 31 L. [2] Demegestone is metabolized by hydroxylation at the C21, C1, C2, and C11 positions, which is eventually followed by A-ring aromatization after 1,2-dehydration. [2] The major metabolite of demegestone is a 21-hydroxy derivative. [2] The metabolic clearance rate of demegestone is 20 L/h. [2] Its biological half-lives are 2.39 and 0.24 hours with intravenous injection. [2] Demegestone and/or its metabolites are excreted, at least in part, in urine. [2]

Chemistry

Demegestone, also known as 17α-methyl-δ9-19-norprogesterone or as 17α-methyl-19-norpregna-4,9-diene-3,20-dione, is a synthetic norpregnane steroid and a derivative of progesterone. [3] [4] [6] It is specifically a combined derivative of 17α-methylprogesterone and 19-norprogesterone, or of 17α-methyl-19-norprogesterone. [3] [4] [6] Related derivatives of 17α-methyl-19-norprogesterone include promegestone and trimegestone. [3] [6]

History

Demegestone was first described in the literature in 1964 and was introduced for medical use in 1974 in France. [3] [4] It was developed by Roussel Uclaf. [4]

Society and culture

Generic names

Demegestone is the generic name of the drug and its INN Tooltip International Nonproprietary Name. [3] It is also known by its developmental code name R-2453 or RU-2453. [3]

Brand names

Demegestone was marketed under the brand name Lutionex. [3] [4]

Availability

Demegestone is no longer marketed and hence is no longer available in any country. [5] It was previously available in France. [5] [4]

Related Research Articles

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

Gestrinone, sold under the brand names Dimetrose and Nemestran among others, is a medication which is used in the treatment of endometriosis. It has also been used to treat other conditions such as uterine fibroids and heavy menstrual bleeding and has been investigated as a method of birth control. Gestrinone is used alone and is not formulated in combination with other medications. It is taken by mouth or in through the vagina.

<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">Norgestrienone</span> Chemical compound

Norgestrienone, sold under the brand names Ogyline, Planor, and Miniplanor, is a progestin medication which has been used in birth control pills, sometimes in combination with ethinylestradiol. It was developed by Roussel Uclaf and has been registered for use only in France. Under the brand name Planor, it has been marketed in France as 2 mg norgestrienone and 50 μg ethinylestradiol tablets. It is taken by mouth.

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

Trestolone, also known as 7α-methyl-19-nortestosterone (MENT), is an experimental androgen/anabolic steroid (AAS) and progestogen medication which has been under development for potential use as a form of hormonal birth control for men and in androgen replacement therapy for low testosterone levels in men but has never been marketed for medical use. It is given as an implant that is placed into fat. As trestolone acetate, an androgen ester and prodrug of trestolone, the medication can also be given by injection into muscle.

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

Metribolone is a synthetic and orally active anabolic–androgenic steroid (AAS) and a 17α-alkylated nandrolone (19-nortestosterone) derivative which was never marketed for medical use but has been widely used in scientific research as a hot ligand in androgen receptor (AR) ligand binding assays (LBAs) and as a photoaffinity label for the AR. More precisely, metribolone is the 17α-methylated derivative of trenbolone. It was investigated briefly for the treatment of advanced breast cancer in women in the late 1960s and early 1970s, but was found to produce signs of severe hepatotoxicity at very low dosages, and its development was subsequently discontinued.

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

Promegestone, sold under the brand name Surgestone, is a progestin medication which is used in menopausal hormone therapy and in the treatment of gynecological disorders. It is taken by mouth.

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

Normethandrone, also known as methylestrenolone or methylnortestosterone and sold under the brand name Metalutin among others, is a progestin and androgen/anabolic steroid (AAS) medication which is used in combination with an estrogen in the treatment of amenorrhea and menopausal symptoms in women. It is taken by mouth.

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

Trimegestone, sold under the brand names Ondeva and Totelle among others, is a progestin medication which is used in menopausal hormone therapy and in the prevention of postmenopausal osteoporosis. It was also under development for use in birth control pills to prevent pregnancy, but ultimately was not marketed for this purpose. The medication is available alone or in combination with an estrogen. It is taken by mouth.

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

Moxestrol, sold under the brand name Surestryl, is an estrogen medication which has been used in Europe for the treatment of menopausal symptoms and menstrual disorders. It is taken by mouth. In addition to its use as a medication, moxestrol has been used in scientific research as a radioligand of the estrogen receptor.

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

Segesterone acetate (SGA), sold under the brand names Nestorone, Elcometrine, and Annovera, is a progestin medication which is used in birth control and in the treatment of endometriosis in the United States, Brazil, and other South American countries. It is available both alone and in combination with an estrogen. It is not effective by mouth and must be given by other routes, most typically as a vaginal ring or implant that is placed into fat.

<span class="mw-page-title-main">19-Norprogesterone</span> Chemical compound

19-Norprogesterone, also known as 19-norpregn-4-ene-3,20-dione, is a steroidal progestin and close analogue of the sex hormone progesterone, lacking only the C19 methyl group of that molecule. It was first synthesized in 1944 in the form of a mixture that also included unnatural stereoisomers of progesterone, and this mixture was found to be at least equivalent to progesterone in terms of progestogenic activity. Subsequent investigations revealed that 17-isoprogesterone and 14-iso-17-isoprogesterone are devoid of progestogenic activity. 19-Norprogesterone was resynthesized in 1951 with an improved method, and was confirmed to be the component of the mixture synthesized in 1944 that was responsible for its progestogenic activity. In 1953, a paper was published showing that 19-norprogesterone possessed 4- to 8-fold the activity of progesterone in the Clauberg assay in rabbits, and at the time of this discovery, 19-norprogesterone was the most potent progestogen known.

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

Methylestradiol, sold under the brand names Ginecosid, Ginecoside, Mediol, and Renodiol, is an estrogen medication which is used in the treatment of menopausal symptoms. It is formulated in combination with normethandrone, a progestin and androgen/anabolic steroid medication. Methylestradiol is taken by mouth.

<span class="mw-page-title-main">17α-Methylprogesterone</span> Chemical compound

17α-Methylprogesterone (17α-MP), or 17α-methylpregn-4-ene-3,20-dione, is a steroidal progestin related to progesterone that was synthesized and characterized in 1949 but was never marketed. Along with ethisterone (1938) and 19-norprogesterone (1951), 17α-MP was one of the earliest derivatives of progesterone to be identified as possessing progestogenic activity. Similarly to progesterone and derivatives like 17α-hydroxyprogesterone and 19-norprogesterone, 17α-MP was found to possess poor oral bioavailability, but showed improved progestogenic activity relative to progesterone when administered via other routes. In addition to its activity as a progestogen, 17α-MP has also been found to possess some antiglucocorticoid activity.

<span class="mw-page-title-main">Dimethyltrienolone</span> Anabolic–androgenic steroid

Dimethyltrienolone is a synthetic, orally active, and extremely potent anabolic–androgenic steroid (AAS) and 17α-alkylated 19-nortestosterone (nandrolone) derivative which was never marketed for medical use. It has among the highest known affinity of any AAS for the androgen receptors, and has been said to be perhaps the most potent AAS to have ever been developed.

<span class="mw-page-title-main">17α-Methyl-19-norprogesterone</span> Chemical compound

17α-Methyl-19-norprogesterone, also known as 17α-methyl-19-norpregn-4-ene-3,20-dione, is a progestin which was never marketed. It is a derivative of progesterone, and is the combined derivative of 17α-methylprogesterone and 19-norprogesterone. The drug is the parent compound of a subgroup of the 19-norprogesterone group of progestins, which includes demegestone, promegestone, and trimegestone.

<span class="mw-page-title-main">RU-16117</span> Chemical compound

RU-16117 is an estrogen medication which was investigated for the potential treatment of symptoms of estrogen deficiency such as hot flashes and osteoporosis in women but was never marketed. It was developed for use by mouth.

<span class="mw-page-title-main">RU-2309</span> Chemical compound

RU-2309, also known as 18-methylmetribolone, δ9,11-17α,18-dimethyl-19-nortestosterone, or 17α,18-dimethylestr-4,9,11-trien-17β-ol-3-one, is a 17α-alkylated androgen/anabolic steroid (AAS) of the 19-nortestosterone group which was never marketed. It is the C18 methyl or C13β ethyl derivative of metribolone. The compound is closely related to tetrahydrogestrinone (THG), which has the same chemical structure as RU-2309 except for possessing an ethyl group at the C17α position instead of a methyl group. Hence, it could also be referred to as 17α-methyl-THG. RU-2309 shows high affinity for the androgen, progesterone, and glucocorticoid receptors.

<span class="mw-page-title-main">7α-Methylestradiol</span> Chemical compound

7α-Methylestradiol (7α-Me-E2), also known as 7α-methylestra-1,3,5(10)-triene-3,17β-diol, is a synthetic estrogen and an active metabolite of the androgen/anabolic steroids trestolone/Methandienone. It is considered to be responsible for the estrogenic activity of trestolone. The compound shows about the same affinity for the estrogen receptor as estradiol.

<span class="mw-page-title-main">5α-Dihydroethisterone</span> Chemical compound

5α-Dihydroethisterone is an active metabolite of the formerly clinically used but now-discontinued progestin ethisterone and the experimental and never-marketed hormonal antineoplastic agent ethynylandrostanediol (HE-3235). Its formation from its parent drugs is catalyzed by 5α-reductase in tissues that express the enzyme in high amounts like the liver, skin, hair follicles, and prostate gland. 5α-DHET has significant affinity for steroid hormone receptors and may contribute importantly to the activities of its parent drugs.

<span class="mw-page-title-main">DU-41165</span> Chemical compound

DU-41165, also known as 6-fluoro-16-methylene-17α-acetoxy-δ6-retroprogesterone, is a progestin which was developed by Philips-Duphar in the 1970s and was never marketed. It is a combined derivative of 17α-hydroxyprogesterone and retroprogesterone. The drug shows extremely high potency as a progestogen in animals. It has been found to possess 158% of the relative binding affinity of promegestone for the progesterone receptor expressed in rat uterus. DU-41165 also showed 28% of the affinity of RU-28362 for the glucocorticoid receptor expressed in rat liver, but no affinity for the mineralocorticoid receptor expressed in rat kidney. The drug showed no androgenic, anabolic, or estrogenic activity in animals, but did show some antiandrogenic and glucocorticoid activity at high doses. Although highly potent in animals, DU-41165 produced little or no progestogenic effect at dosages of 50 and 200 µg/day in women, suggesting major species differences. DU-41165 has been studied as a potential photoaffinity label for the progesterone receptor.

References

  1. 1 2 3 Iizuka R, Hayashi M, Kamouchi Y, Yamanaka K (1971). "Evaluation of a low-dose progestagen as a contraceptive". Nihon Funin Gakkai Zasshi. 16 (1): 68–82. PMID   12158578.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Raynaud JP, Cousty C, Salmon J (1974). "121. Metabolic studies of R2453, a highly potent progestin". Journal of Steroid Biochemistry. 5 (4): 324. doi:10.1016/0022-4731(74)90266-0. ISSN   0022-4731.
  3. 1 2 3 4 5 6 7 8 9 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 356–. ISBN   978-1-4757-2085-3.
  4. 1 2 3 4 5 6 7 8 9 William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Elsevier. pp. 1215–. ISBN   978-0-8155-1856-3.
  5. 1 2 3 4 "Demegestone". Micromedex.: [ permanent dead link ]
  6. 1 2 3 4 5 6 Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID   16112947. S2CID   24616324.
  7. 1 2 Pugeat M, Lejeune H, Dechaud H, Brébant C, Mallein R, Tourniaire J (1988). "[Luteal insufficiency and elevation of sex-binding proteins by demegestone]". Revue Française de Gynécologie et d'Obstétrique (in French). 83 (7–9): 495–498. PMID   3194612.
  8. 1 2 Lee DL, Kollman PA, Marsh FJ, Wolff ME (September 1977). "Quantitative relationships between steroid structure and binding to putative progesterone receptors". Journal of Medicinal Chemistry. 20 (9): 1139–1146. doi:10.1021/jm00219a006. PMID   926114.
  9. ↑ Hamada H, Nagao H, Toyoda H, Hayashi H, Akihiro L, Kotaki S (1970). "[Clinical observation on oral contraceptive effect by R-2453 (Abstracts of Papers Presented at Showa 44 in the field of gynecology])". Japanese Journal of Obstetrics and Gynecology-Acta Obstetrica et Gynaecologica Japonica. 22 (7): 753.
  10. ↑ Levrier M (January 1979). "Treatment of Ovarian Sterility with Combined Moxestrol-Demegestone Preparation". Journal de Gynécologie Obstétrique et Biologie de la Reproduction. Paris, France: Masson Editeur. 8 (1): 89.
  11. ↑ Rabe T, Goeckenjan M, Ahrendt HJ, Crosignani PG, Dinger JC, Mueck AO, et al. (October 2011). "Oral Contraceptive Pills: Combinations, Dosages and the Rationale behind 50 Years or Oral Hormonal Contraceptive Development" (PDF). Journal für Reproduktionsmedizinund Endokrinologie. 8 (1): 58–129.
  12. ↑ Raynaud JP, Ojasoo T, Labrie F (1981). "Steroid hormones—agonists and antagonists". Mechanisms of Steroid Action. pp. 145–158. doi:10.1007/978-1-349-81345-2_11. ISBN   978-1-349-81347-6.
  13. 1 2 Delettré J, Mornon JP, Lepicard G, Ojasoo T, Raynaud JP (January 1980). "Steroid flexibility and receptor specificity". Journal of Steroid Biochemistry. 13 (1): 45–59. doi:10.1016/0022-4731(80)90112-0. PMID   7382482.
  14. ↑ Dausse JP, Duval D, Meyer P, Gaignault JC, Marchandeau C, Raynaud JP (September 1977). "The relationship between glucocorticoid structure and effects upon thymocytes". Molecular Pharmacology. 13 (5): 948–955. PMID   895725.
  15. ↑ Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, et al. (January 1980). "Steroid hormone receptors and pharmacology". Journal of Steroid Biochemistry. 12: 143–157. doi:10.1016/0022-4731(80)90264-2. PMID   7421203.
  16. ↑ Ojasoo T, Raynaud JP, Doé JC (January 1994). "Affiliations among steroid receptors as revealed by multivariate analysis of steroid binding data". The Journal of Steroid Biochemistry and Molecular Biology. 48 (1): 31–46. doi:10.1016/0960-0760(94)90248-8. PMID   8136304. S2CID   21336380.
  17. ↑ Ojasoo T, Raynaud JP (November 1978). "Unique steroid congeners for receptor studies". Cancer Research. 38 (11 Pt 2): 4186–4198. PMID   359134.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.