Demegestone

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Demegestone
Skeletal formula of demegestone
Ball-and-stick model of the demegestone molecule
Clinical data
Trade namesLutionex
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 classProgestin; Progestogen
ATC code
Pharmacokinetic data
BioavailabilityGood[2]
MetabolismHydroxylation, others[2]
Metabolites• 21-Hydroxydemegestone[2]
• Others[2]
ExcretionUrine[2]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard100.030.278 Edit this at Wikidata
Chemical and physical data
FormulaC21H28O2
Molar mass312.446 g/mol g·mol−1
3D model (JSmol)

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]

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[edit]

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[edit]

Pharmacology[edit]

Pharmacodynamics[edit]

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 AR ER GR MR SHBG CBG
Demegestone 230 1 0 5 1–2 ? ?
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PR, testosterone for the AR, E2 for the ER, DEXA for the GR, aldosterone for the MR, DHT for SHBG, and cortisol for CBG. Sources: [13][15][16][17]

Pharmacokinetics[edit]

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[edit]

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[edit]

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[edit]

Generic names[edit]

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

Brand names[edit]

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

Availability[edit]

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

References[edit]

  1. ^ a b c 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. ^ a b c d e f g h i j k l m n o p q r s Raynaud, J.P.; 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. ^ a b c d e f g h i J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 356–. ISBN 978-1-4757-2085-3.
  4. ^ a b c d e f g h i William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1215–. ISBN 978-0-8155-1856-3.
  5. ^ a b c d http://www.micromedexsolutions.com/micromedex2/[permanent dead link]
  6. ^ a b c d e f Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  7. ^ a b Pugeat M, Lejeune H, Dechaud H, Brébant C, Mallein R, Tourniaire J (1988). "[Luteal insufficiency and elevation of sex-binding proteins by demegestone]". Rev Fr Gynecol Obstet (in French). 83 (7–9): 495–8. PMID 3194612.
  8. ^ a b Lee DL, Kollman PA, Marsh FJ, Wolff ME (September 1977). "Quantitative relationships between steroid structure and binding to putative progesterone receptors". J. Med. Chem. 20 (9): 1139–46. 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. https://ci.nii.ac.jp/naid/110002126113/
  10. ^ Levrier, M. (1979, January). Treatment of Ovarian Sterility with Combined Moxestrol-Demegestone Preparation. In Journal De Gynecologie Obstetrique Et Biologie De La Reproduction (Vol. 8, No. 1, Pp. 89–89). 120 Blvd Saint-Germain, 75280 Paris 06, France: Masson Editeur.
  11. ^ Rabe, T., Goeckenjan, M., Ahrendt, H. J., Crosignani, P. G., Dinger, J. C., Mueck, A. O., ... & Strowitzki, T. (2011). Oral Contraceptive Pills: Combinations, Dosages and the Rationale behind 50 Years or Oral Hormonal Contraceptive Development. Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology, 8(1), 58-129. http://www.kup.at/kup/pdf/10166.pdf
  12. ^ Raynaud, J. P.; Ojasoo, T.; Labrie, F. (1981). "Steroid hormones—agonists and antagonists": 145–158. doi:10.1007/978-1-349-81345-2_11. Cite journal requires |journal= (help)
  13. ^ a b Delettré J, Mornon JP, Lepicard G, Ojasoo T, Raynaud JP (January 1980). "Steroid flexibility and receptor specificity". J. Steroid Biochem. 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". Mol. Pharmacol. 13 (5): 948–55. PMID 895725.
  15. ^ Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, Labrie F, Mornon JP (January 1980). "Steroid hormone receptors and pharmacology". J. Steroid Biochem. 12: 143–57. 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". J. Steroid Biochem. Mol. Biol. 48 (1): 31–46. doi:10.1016/0960-0760(94)90248-8. PMID 8136304.
  17. ^ Ojasoo T, Raynaud JP (November 1978). "Unique steroid congeners for receptor studies". Cancer Res. 38 (11 Pt 2): 4186–98. PMID 359134.