{{Short description|Chemical compound}} {{Infobox drug | IUPAC_name = (8''S'',13''S'',14''S'',17''S'')-17-acetyl-13,17-dimethyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[''a'']phenanthren-3-one | image = Demegestone.svg | image_class = skin-invert-image | width = 215px | alt = Skeletal formula of demegestone | image2 = Demegestone 3D ball.png | image_class2 = bg-transparent | width2 = 225px | alt2 = Ball-and-stick model of the demegestone molecule

<!--Clinical data--> | tradename = Lutionex | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_US = <!-- A / B / C / D / X --> | pregnancy_category = | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> | legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> | legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> | legal_status = | routes_of_administration = By mouth<ref name="pmid12158578" /> | class = Progestogen; Progestin

<!--Pharmacokinetic data--> | bioavailability = Good<ref name="RaynaudCousty1974" /> | protein_bound = | metabolism = Hydroxylation, others<ref name="RaynaudCousty1974" /> | metabolites = • 21-Hydroxydemegestone<ref name="RaynaudCousty1974" /><br />• Others<ref name="RaynaudCousty1974" /> | elimination_half-life = | excretion = Urine<ref name="RaynaudCousty1974" />

<!--Identifiers--> | CAS_number = 10116-22-0 | ATC_prefix = G03 | ATC_suffix = DB05 | PubChem = 93057 | DrugBank = | ChemSpiderID = 84009 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 6E89AM91SZ | ChEBI = 135339 | ChEMBL = 2104231 | KEGG = D07223 | synonyms = Dimegestone; R-2453; RU-2453; 17α-Methyl-δ<sup>9</sup>-19-norprogesterone; 17α-Methyl-19-norpregna-4,9-diene-3,20-dione

<!--Chemical data--> | C=21 | H=28 | O=2 | SMILES = CC(=O)[C@]1(CC[C@@H]2[C@@]1(CCC3=C4CCC(=O)C=C4CC[C@@H]23)C)C | StdInChI = 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 | StdInChIKey = JWAHBTQSSMYISL-MHTWAQMVSA-N }} <!-- Definition and medical uses --> '''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.<ref name="Elks2014">{{cite book | vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA356|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=356–}}</ref><ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia | edition = 3rd |url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1215|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1215–}}</ref><ref name="Micromedex">{{cite web | url = http://www.micromedexsolutions.com/micromedex2/ | title = Demegestone | work = Micromedex}}: {{Dead link|date=July 2019 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref><ref name="pmid3194612" /> It is taken by mouth.<ref name="RaynaudCousty1974" /><ref name="pmid12158578">{{cite journal | vauthors = Iizuka R, Hayashi M, Kamouchi Y, Yamanaka K | title = Evaluation of a low-dose progestagen as a contraceptive | journal = Nihon Funin Gakkai Zasshi | volume = 16 | issue = 1 | pages = 68–82 | date = 1971 | pmid = 12158578 }}</ref>

<!-- Side effects and mechanism --> Demegestone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.<ref name="pmid16112947" /><ref name="RaynaudCousty1974" /><ref name="pmid926114">{{cite journal | vauthors = Lee DL, Kollman PA, Marsh FJ, Wolff ME | title = Quantitative relationships between steroid structure and binding to putative progesterone receptors | journal = Journal of Medicinal Chemistry | volume = 20 | issue = 9 | pages = 1139–1146 | date = September 1977 | pmid = 926114 | doi = 10.1021/jm00219a006 }}</ref> It has no androgenic activity.<ref name="RaynaudCousty1974" />

<!-- History, society, and culture --> Demegestone was first described in 1966 and was introduced for medical use in France in 1974.<ref name="Elks2014" /><ref name="Publishing2013" /> It has only been marketed in France, and has since been discontinued in this country.<ref name="Micromedex" /><ref name="Publishing2013" />

==Medical uses== Demegestone has been used to treat luteal insufficiency.<ref name="pmid3194612">{{cite journal | vauthors = Pugeat M, Lejeune H, Dechaud H, Brébant C, Mallein R, Tourniaire J | title = [Luteal insufficiency and elevation of sex-binding proteins by demegestone] | language = fr | journal = Revue Française de Gynécologie et d'Obstétrique | volume = 83 | issue = 7–9 | pages = 495–498 | date = 1988 | pmid = 3194612 }}</ref> It has also been studied in combination with estrogens, such as moxestrol, as an oral contraceptive and treatment for infertility.<ref name="pmid12158578" /><ref name="HamadaNagao1970">{{cite journal | vauthors = Hamada H, Nagao H, Toyoda H, Hayashi H, Akihiro L, Kotaki S | date = 1970 | title = [Clinical observation on oral contraceptive effect by R-2453 (Abstracts of Papers Presented at Showa 44 in the field of gynecology]). | journal = Japanese Journal of Obstetrics and Gynecology-Acta Obstetrica et Gynaecologica Japonica | volume = 22 | issue = 7 | pages = 753 | url = https://ci.nii.ac.jp/naid/110002126113/ }}</ref><ref name="Levrier1979">{{cite journal | vauthors = Levrier M | date = January 1979 | title = Treatment of Ovarian Sterility with Combined Moxestrol-Demegestone Preparation. | journal = Journal de Gynécologie Obstétrique et Biologie de la Reproduction | volume = 8 | issue = 1 | pages = 89 | location = Paris, France | publisher = Masson Editeur }}</ref>

==Side effects== {{See also|Progestin#Side effects}}

==Pharmacology==

===Pharmacodynamics=== Demegestone is a progestogen, and hence is an agonist of the progesterone receptor (PR).<ref name="pmid16112947" /><ref name="pmid926114" /><ref name="RaynaudCousty1974">{{cite journal| vauthors = Raynaud JP, Cousty C, Salmon J|title=121. Metabolic studies of R2453, a highly potent progestin|journal=Journal of Steroid Biochemistry|volume=5|issue=4|year=1974|pages=324|issn=0022-4731|doi=10.1016/0022-4731(74)90266-0}}</ref> It is a highly potent progestogen, showing 50&nbsp;times the potency of progesterone in the Clauberg test.<ref name="RaynaudCousty1974" /> The ovulation-inbhiting dosage of demegestone is 2.5&nbsp;mg/day, while the endometrial transformation dosage is 100&nbsp;mg per cycle.<ref name="RabeGoeckenjan2011">{{cite journal | vauthors = Rabe T, Goeckenjan M, Ahrendt HJ, Crosignani PG, Dinger JC, Mueck AO, Lohr PA, Creinin MD, Sabatini R, Strowitzki T | display-authors = 6 | title = Oral Contraceptive Pills: Combinations, Dosages and the Rationale behind 50 Years or Oral Hormonal Contraceptive Development | journal = Journal für Reproduktionsmedizinund Endokrinologie | date = October 2011 | volume = 8 | issue = 1 | pages = 58–129 | url = https://www.kup.at/kup/pdf/10166.pdf }}</ref> The medication is devoid of androgenic activity,<ref name="RaynaudCousty1974" /> and instead has some antiandrogenic activity.<ref name="RaynaudOjasoo1981">{{cite book | vauthors = Raynaud JP, Ojasoo T, Labrie F |title=Mechanisms of Steroid Action|chapter=Steroid hormones—agonists and antagonists|year=1981|pages=145–158|publisher=Macmillan Education UK |doi=10.1007/978-1-349-81345-2_11|isbn=978-1-349-81347-6}}</ref> Demegestone has low affinity for the glucocorticoid receptor.<ref name="pmid7382482" /> In a particular bioassay, both demegestone and progesterone showed antiglucocorticoid rather than glucocorticoid activity.<ref name="pmid895725">{{cite journal | vauthors = Dausse JP, Duval D, Meyer P, Gaignault JC, Marchandeau C, Raynaud JP | title = The relationship between glucocorticoid structure and effects upon thymocytes | journal = Molecular Pharmacology | volume = 13 | issue = 5 | pages = 948–955 | date = September 1977 | pmid = 895725 }}</ref> The major metabolite of demegestone, a 21-hydroxylated metabolite, is a moderately potent progestogen (4&nbsp;times the potency of progesterone) and a weak mineralocorticoid (2% of the potency of deoxycorticosterone).<ref name="RaynaudCousty1974" />

{| class="wikitable mw-collapsible mw-collapsed" style="text-align:left; margin-left:auto; margin-right:auto; border:none;" |+ class="nowrap" | Relative affinities (%) of demegestone |- ! Compound || {{abbrlink|PR|Progesterone receptor}} || {{abbrlink|AR|Androgen receptor}} || {{abbrlink|ER|Estrogen receptor}} || {{abbrlink|GR|Glucocorticoid receptor}} || {{abbrlink|MR|Mineralocorticoid receptor}} || {{abbrlink|SHBG|Sex hormone-binding globulin}} || {{abbrlink|CBG|Corticosteroid binding globulin}} |- | Demegestone || 230 || 1 || 0 || 5 || 1–2 || ? || ? |- class="sortbottom" | colspan="9" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' Values are percentages (%). Reference ligands (100%) were progesterone for the {{abbrlink|PR|progesterone receptor}}, testosterone for the {{abbrlink|AR|androgen receptor}}, {{abbr|E2|estradiol}} for the {{abbrlink|ER|estrogen receptor}}, {{abbrlink|DEXA|dexamethasone}} for the {{abbrlink|GR|glucocorticoid receptor}}, aldosterone for the {{abbrlink|MR|mineralocorticoid receptor}}, {{abbrlink|DHT|dihydrotestosterone}} for {{abbrlink|SHBG|sex hormone-binding globulin}}, and cortisol for {{abbrlink|CBG|Corticosteroid-binding globulin}}. '''Sources:''' <ref name="pmid7382482">{{cite journal | vauthors = Delettré J, Mornon JP, Lepicard G, Ojasoo T, Raynaud JP | title = Steroid flexibility and receptor specificity | journal = Journal of Steroid Biochemistry | volume = 13 | issue = 1 | pages = 45–59 | date = January 1980 | pmid = 7382482 | doi = 10.1016/0022-4731(80)90112-0 }}</ref><ref name="pmid7421203">{{cite journal | vauthors = Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, Labrie F, Mornon JP | display-authors = 6 | title = Steroid hormone receptors and pharmacology | journal = Journal of Steroid Biochemistry | volume = 12 | pages = 143–157 | date = January 1980 | pmid = 7421203 | doi = 10.1016/0022-4731(80)90264-2 }}</ref><ref name="pmid8136304">{{cite journal | vauthors = Ojasoo T, Raynaud JP, Doé JC | title = Affiliations among steroid receptors as revealed by multivariate analysis of steroid binding data | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 48 | issue = 1 | pages = 31–46 | date = January 1994 | pmid = 8136304 | doi = 10.1016/0960-0760(94)90248-8 | s2cid = 21336380 }}</ref><ref name="pmid359134">{{cite journal | vauthors = Ojasoo T, Raynaud JP | title = Unique steroid congeners for receptor studies | journal = Cancer Research | volume = 38 | issue = 11 Pt 2 | pages = 4186–4198 | date = November 1978 | pmid = 359134 }}</ref> |}

===Pharmacokinetics=== Demegestone has good bioavailability.<ref name="RaynaudCousty1974" /> The initial volume of distribution of demegestone is 31&nbsp;L.<ref name="RaynaudCousty1974" /> 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.<ref name="RaynaudCousty1974" /> The major metabolite of demegestone is a 21-hydroxy derivative.<ref name="RaynaudCousty1974" /> The metabolic clearance rate of demegestone is 20&nbsp;L/h.<ref name="RaynaudCousty1974" /> Its biological half-lives are 2.39 and 0.24&nbsp;hours with intravenous injection.<ref name="RaynaudCousty1974" /> Demegestone and/or its metabolites are excreted, at least in part, in urine.<ref name="RaynaudCousty1974" />

==Chemistry== {{See also|List of progestogens}}

Demegestone, also known as 17α-methyl-δ<sup>9</sup>-19-norprogesterone or as 17α-methyl-19-norpregna-4,9-diene-3,20-dione, is a synthetic norpregnane steroid and a derivative of progesterone.<ref name="Elks2014" /><ref name="Publishing2013" /><ref name="pmid16112947" /> It is specifically a combined derivative of 17α-methylprogesterone and 19-norprogesterone, or of 17α-methyl-19-norprogesterone.<ref name="Elks2014" /><ref name="Publishing2013" /><ref name="pmid16112947" /> Related derivatives of 17α-methyl-19-norprogesterone include promegestone and trimegestone.<ref name="Elks2014" /><ref name="pmid16112947" />

==History== Demegestone was first described in the literature in 1964 and was introduced for medical use in 1974 in France.<ref name="Elks2014" /><ref name="Publishing2013" /> It was developed by Roussel Uclaf.<ref name="Publishing2013" />

==Society and culture==

===Generic names=== ''Demegestone'' is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}.<ref name="Elks2014" /> It is also known by its developmental code name ''R-2453'' or ''RU-2453''.<ref name="Elks2014" />

===Brand names=== Demegestone was marketed under the brand name Lutionex.<ref name="Elks2014" /><ref name="Publishing2013" />

===Availability=== Demegestone is no longer marketed and hence is no longer available in any country.<ref name="Micromedex" /> It was previously available in France.<ref name="Micromedex" /><ref name="Publishing2013" />

== References == {{Reflist}}

{{Progestogens and antiprogestogens}} {{Navboxes | title = Pharmacodynamics | titlestyle = background:#ccccff | list1 = {{Androgen receptor modulators}} {{Glucocorticoid receptor modulators}} {{Progesterone receptor modulators}} }}

Category:Abandoned drugs Category:Antiandrogens Category:Conjugated dienes Category:Diketones Category:Enones Category:Norpregnanes Category:Progestogens