Altrenogest

{{Short description|Chemical compound}} {{Drugbox | Verifiedfields = | Watchedfields = | verifiedrevid = | IUPAC_name = (8''S'',13''S'',14''S'',17''R'')-17-Hydroxy-13-methyl-17-prop-2-enyl-1,2,6,7,8,14,15,16-octahydrocyclopenta[''a'']phenanthren-3-one | image = Altrenogest.svg | image_class = skin-invert-image | width = 225 | alt =

| tradename = Regumate, Matrix | pregnancy_AU =  | pregnancy_category = | routes_of_administration = By mouth<ref name="AsaPorton2005">{{cite book| vauthors = Asa CS | chapter = Types of contraception: The Choices | veditors = Asa CS, Porton IJ |title=Wildlife Contraception: Issues, Methods, and Applications| chapter-url=https://books.google.com/books?id=ydFciujnWTcC&pg=PA35|date=24 August 2005|publisher=JHU Press|isbn=978-0-8018-8304-0|pages=35–}}</ref> | class = Progestogen; Progestin | ATCvet = yes | ATC_prefix = G03 | ATC_suffix = DX90

| legal_AU =  | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Health product highlights 2021: Annexes of products approved in 2021 | website=Health Canada | date=3 August 2022 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-product-highlights-2021/appendices.html | access-date=25 March 2024}}</ref> | legal_UK = | legal_US = | legal_status =

| C=21 | H=26 | O=2 | SMILES = C[C@]12C=CC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CC[C@]2(CC=C)O | StdInChI_Ref = | StdInChI = 1S/C21H26O2/c1-3-10-21(23)12-9-19-18-6-4-14-13-15(22)5-7-16(14)17(18)8-11-20(19,21)2/h3,8,11,13,18-19,23H,1,4-7,9-10,12H2,2H3/t18-,19+,20+,21+/m1/s1 | StdInChIKey_Ref = | StdInChIKey = VWAUPFMBXBWEQY-ANULTFPQSA-N }}

'''Altrenogest''', sold under the brand names '''Swinemate''' and '''Altren''' manufactured by Aurora Pharmaceutical and '''Regumate''' manufactured by Merck, is a progestin of the 19-nortestosterone group which is widely used in veterinary medicine to suppress or synchronize estrus in horses and pigs.<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=PA35|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=35–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA33|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=33–}}</ref><ref name="Drugs.com">{{Cite web |url=https://www.drugs.com/international/altrenogest.html |title=Altrenogest | work = Drugs.com |access-date=2017-11-25 |archive-date=2017-12-01 |archive-url=https://web.archive.org/web/20171201030601/https://www.drugs.com/international/altrenogest.html |url-status=dead }}</ref><ref name="RivierePapich2013">{{cite book| vauthors = Reddy DS, Gadsby JE | chapter = Hormones Affecting Reproduction | veditors = Riviere JE, Papich MG |title=Veterinary Pharmacology and Therapeutics| chapter-url = https://books.google.com/books?id=xAPa4WDzAnQC&pg=PA727|date=13 May 2013|publisher=John Wiley & Sons|isbn=978-1-118-68590-7|pages=727–}}</ref><ref name="Zeelen1990">{{cite book| vauthors = Zeelen FJ |title=Medicinal chemistry of steroids|url=https://books.google.com/books?id=px9tAAAAMAAJ|year=1990|publisher=Elsevier Science Limited|isbn=978-0-444-88727-6|pages=108–109|quote=Other examples are allylestrenol (42), a pro-drug converted to the 3-keto analogue (43), which is used in the treatment of threatened abortion [78,79] and altrenogest (44), used in sows and mares to suppress ovulation and estrus behaviour [80]. [...] Progestins with a 17a-allyl side chain: (42) allylestrenol, (43), (44) altrenogest.}}</ref> It is available for veterinary use in both Europe (as Regumate) and the United States (as Matrix).<ref name="Rodriguez-Martinez2010">{{cite book| vauthors = Rodriguez-Martinez H |title=Control of Pig Reproduction VIII|url=https://books.google.com/books?id=em-TrWgAFSYC&pg=PA189|date=1 April 2010|publisher=Nottingham University Press|isbn=978-1-907284-53-3|pages=189–}}</ref>

==Uses==

===Veterinary=== Altrenogest is used in veterinary medicine.

==Pharmacology==

===Pharmacodynamics=== An ''in vitro'' yeast structure–activity relationships bioassay study found that altrenogest was the most potent agonist of both the progesterone receptor (PR) and the androgen receptor (AR) of a large selection of other progestogens as well as anabolic–androgenic steroids (AAS).<ref name="pmid18395441">{{cite journal | vauthors = McRobb L, Handelsman DJ, Kazlauskas R, Wilkinson S, McLeod MD, Heather AK | title = Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 110 | issue = 1–2 | pages = 39–47 | date = May 2008 | pmid = 18395441 | doi = 10.1016/j.jsbmb.2007.10.008 | s2cid = 5612000 }}</ref> The observed potency of altrenogest even exceeded that of metribolone (methyltrienolone, R-1881), which was the second most potent compound.<ref name="pmid18395441" /> In the study, it showed an EC50 of 0.64 nM for the AR and 688% of the relative activational potency of testosterone and an EC50 of 0.3 nM and 1,300% of the relative activational potency of progesterone, with an AR/PR activational potency ratio of 0.53.<ref name="pmid18395441" />

Although very potent in both activities ''in vitro'', the AR/PR activational potency ratio of altrenogest was in the same range as that of other 19-nortestosterone progestins such as norethisterone, noretynodrel, norgestrel, and allylestrenol (ratio for all < 1.0), whereas the AR/PR activational potency ratio of its 17α-deallylated AAS analogue trenbolone was, at 64, profoundly increased (although the ratio of metribolone (the 17α-methylated variant of altrenogest), at 0.56, was almost the same as that of altrenogest).<ref name="pmid18395441" />

According to its manufacturer Roussel Uclaf, altrenogest has weak anabolic and androgenic activity equivalent to 1/20th of that of testosterone.<ref name="pmid3131291">{{cite journal | vauthors = Kluber EF, Minton JE, Stevenson JS, Hunt MC, Davis DL, Hoagland TA, Nelssen JL | title = Growth, carcass traits, boar odor and testicular and endocrine functions of male pigs fed a progestogen, altrenogest | journal = Journal of Animal Science | volume = 66 | issue = 2 | pages = 470–478 | date = February 1988 | pmid = 3131291 | doi = 10.2527/jas1988.662470x }}</ref> However, no significant androgenic effects have been observed in young stallions or mature mares,<ref name="McKinnonSquires2011" /> and altrenogest has notably been used to maintain pregnancy in mares (similarly to the use of allylestrenol to maintain pregnancy in women) with no incidence of virilization or other abnormalities in filly offspring.<ref name="ProgramResources2013">{{cite book|author1=Committee to Review the Bureau of Land Management Wild Horse and Burro Management Program|author2=Board on Agriculture and Natural Resources|author3=Division on Earth and Life Studies|author4=National Research Council|title=Using Science to Improve the BLM Wild Horse and Burro Program: A Way Forward|url=https://books.google.com/books?id=0T5eAgAAQBAJ&pg=PA120|date=4 October 2013|publisher=National Academies Press|isbn=978-0-309-26494-5|pages=120–}}</ref> On the other hand, minor potential anabolic/androgenic effects have been suggested for altrenogest in pigs.<ref name="McKinnonSquires2011" />

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

Altrenogest, also known as 17α-allyl-19-nor-δ9,11-testosterone or as 17α-allylestra-4,9,11-trien-17β-ol-3-one, is a synthetic estrane steroid and derivative of 19-nortestosterone and 17α-allyltestosterone, or of 17α-allyl-19-nortestosterone.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Zeelen1990" /> It is one of only two marketed progestins that possesses a 17α-allyl group, the other being allylestrenol.<ref name="Elks2014" /><ref name="IndexNominum2000" /> Most other progestins possess a 17α-ethynyl group, while AAS, if they are 17α-substituted, are usually 17α-alkylated (with a methyl or ethyl group).<ref name="Elks2014" /><ref name="IndexNominum2000" /> Altrenogest is the 17α-allylated derivative of the AAS trenbolone (and hence can also be referred to as allyltrenbolone or allyltrienolone), which itself is the 9,11-didehydro analogue of the AAS nandrolone (19-nortestosterone).<ref name="Elks2014" /><ref name="IndexNominum2000" /> Altrenogest is also closely related to norgestrienone.<ref name="Elks2014" /><ref name="IndexNominum2000" /> ===Synthesis=== The chemical synthesis has been described:<ref>Liu Xirong, et al. CN117106002 (2023 to Hunan Xinhexin Biological Medicine Co ltd).</ref> Prior art:<ref>高伟, et al. CN106946961 (2017 to Prompt Bio Tech Ltd Of Xiamen Allred).</ref><ref>Qian Xingyu, et al. CN106810584 (2017 to Ningbo Second Hormone Factory).</ref> 20th century methods:<ref>DE1618810 idem Daniel Bertin, Andre Pierdet, US3484462 (1969 to Roussel Uclaf).</ref><ref>, FR5183M (1967-06-19).</ref>

center|500px|class=skin-invert-image

Dienedione is converted to its dimethylacetal to give 3,3-dimethoxyestra-5(10),9(11)-dien-17-one [10109-76-9] ('''1'''). Grignard reaction with allyl chloride [107-05-1] gives PC14988798 ('''2'''). Deprotection of the acetal using an aqueous solution of potassium bisulfate gives PC14988800 ('''3'''). Oxidation with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone [84-58-2] completed the synthesis of altrenogest ('''4''').

==History== Altrenogest has been marketed as Regumate since the early 1980s.<ref name="McKinnonSquires2011">{{cite book| vauthors = McKinnon AO, Squires EL, Vaala WE, Varner DD |title=Equine Reproduction |url= https://books.google.com/books?id=QPJQT6-g-YMC&pg=PT4462|date=5 July 2011|publisher=John Wiley & Sons|isbn=978-0-470-96187-2|pages=4462–}}</ref>

==Society and culture==

===Generic names=== ''Altrenogest'' is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|BAN|British Approved Name}}, while ''altrénogest'' is its {{abbrlink|DCF|Dénomination Commune Française}}.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" />

===Brand names=== Altrenogest is marketed under the brand names Regumate and Matrix among others.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" />

== References == {{Reflist}}

Category:Tertiary alcohols Category:Allyl compounds Category:Estranes Category:Enones Category:Progestogens Category:Veterinary drugs Category:Polyenes