{{Short description|Chemical compound}} {{Drugbox | Verifiedfields = verified | Watchedfields = verified | verifiedrevid = 462252160 | IUPAC_name = (7''R'',8''R'',9''S'',10''R'',13''S'',14''S'',17''S'')-17-hydroxy-7,13,17-trimethyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[''a'']phenanthren-3-one | image = Mibolerone structure.png | image_class = skin-invert-image | width = 225px | image2 = Mibolerone molecule ball.png | image_class2 = bg-transparent | width2 = 235px
<!--Clinical data--> | tradename = Cheque Drops, Matenon | Drugs.com = {{drugs.com|international|mibolerone}} | pregnancy_category = | legal_BR = C5 | legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-15 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}</ref> | legal_CA = Schedule IV | legal_US = Schedule III | legal_status = | routes_of_administration = By mouth | class = Androgen; Anabolic steroid; Progestogen
<!--Pharmacokinetic data--> | bioavailability = | protein_bound = | metabolism = Liver | elimination_half-life = | excretion =
<!--Identifiers--> | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 3704-09-4 | ATC_prefix = None | ATC_suffix = | PubChem = 251636 | IUPHAR_ligand = 2859 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 220460 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 9OGY4BOR8D | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D05025 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 34849 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 425863 | synonyms = U-10997; CDB-904; Dimethylnandrolone; Dimethylnortestosterone;<ref name="MortonHall1999">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=mqaOMOtk61IC&pg=PA181|date=31 October 1999|publisher=Springer Science & Business Media|isbn=978-0-7514-0499-9|pages=181–}}</ref> DMNT; 7α,17α-Dimethyl-19-nortestosterone; 7α,17α-Dimethylestr-4-en-17β-ol-3-one
<!--Chemical data--> | C=20 | H=30 | O=2 | SMILES = C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]3[C@@H]1[C@@H]4CC[C@]([C@]4(CC3)C)(C)O | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C20H30O2/c1-12-10-13-11-14(21)4-5-15(13)16-6-8-19(2)17(18(12)16)7-9-20(19,3)22/h11-12,15-18,22H,4-10H2,1-3H3/t12-,15+,16-,17+,18-,19+,20+/m1/s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = PTQMMNYJKCSPET-OMHQDGTGSA-N }}
'''Mibolerone''', also known as '''dimethylnortestosterone''' ('''DMNT''') and sold under the brand names '''Cheque Drops''' and '''Matenon''', is a synthetic, orally active, and extremely potent anabolic–androgenic steroid (AAS) and a 17α-alkylated nandrolone (19-nortestosterone) derivative which was marketed by Upjohn for use as a veterinary drug.<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=PA822|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=822–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA689|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=689–}}</ref><ref name="Llewellyn2011">{{cite book|author=William Llewellyn|title=Anabolics|url=https://books.google.com/books?id=afKLA-6wW0oC&pg=PT395|year=2011|publisher=Molecular Nutrition Llc|isbn=978-0-9828280-1-4|pages=395–}}</ref> It was indicated specifically as an oral treatment for prevention of estrus (heat) in adult female dogs.<ref name="Elks2014" />
==Side effects== {{See also|Anabolic steroid#Adverse effects}}
==Pharmacology==
===Pharmacodynamics=== Mibolerone has both higher affinity and greater selectivity for the androgen receptor (AR) than does the related potent AAS metribolone (17α-methyl-19-nor-δ<sup>9,11</sup>-testosterone),<ref name="pmid2422638">{{cite journal |vauthors=Murthy LR, Johnson MP, Rowley DR, Young CY, Scardino PT, Tindall DJ | title = Characterization of steroid receptors in human prostate using mibolerone | journal = Prostate | volume = 8 | issue = 3 | pages = 241–53 | year = 1986 | pmid = 2422638 | doi = 10.1002/pros.2990080305| s2cid = 43768386 }}</ref><ref name="pmid6333679">{{cite journal |vauthors=Schilling K, Liao S | title = The use of radioactive 7 alpha, 17 alpha-dimethyl-19-nortestosterone (mibolerone) in the assay of androgen receptors | journal = Prostate | volume = 5 | issue = 6 | pages = 581–8 | year = 1984 | pmid = 6333679 | doi =10.1002/pros.2990050603 | s2cid = 86370224 }}</ref> although potent and significant progestogenic activity remains present.<ref name="pmid9228646" /> However, another study found that mibolerone and metribolone had similar affinity for the progesterone receptor (PR) but that mibolerone only had around half the affinity of metribolone for the AR.<ref name="pmid1291626">{{cite journal | vauthors = Loughney DA, Schwender CF | title = A comparison of progestin and androgen receptor binding using the CoMFA technique | journal = J. Comput.-Aided Mol. Des. | volume = 6 | issue = 6 | pages = 569–81 | year = 1992 | pmid = 1291626 | doi = 10.1007/bf00126215| bibcode = 1992JCAMD...6..569L | s2cid = 22004130 }}</ref>
{| class="wikitable center sortable mw-collapsible mw-collapsed" style="width:600px; text-align:left; margin-left:auto; margin-right:auto; border:none;" |+ class="nowrap" | Relative affinities (%) of mibolerone and related steroids<ref name="pmid7382482">{{cite journal | vauthors = Delettré J, Mornon JP, Lepicard G, Ojasoo T, Raynaud JP | title = Steroid flexibility and receptor specificity | journal = J. Steroid Biochem. | volume = 13 | issue = 1 | pages = 45–59 | date = January 1980 | pmid = 7382482 | doi = 10.1016/0022-4731(80)90112-0 }}</ref><ref name="pmid3695484">{{cite journal | vauthors = Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP | title = Towards the mapping of the progesterone and androgen receptors | journal = J. Steroid Biochem. | volume = 27 | issue = 1–3 | pages = 255–69 | date = 1987 | pmid = 3695484 | doi = 10.1016/0022-4731(87)90317-7 }}</ref> |- ! Compound || Chemical name || {{abbrlink|PR|Progesterone receptor}} || {{abbrlink|AR|Androgen receptor}} || {{abbrlink|ER|Estrogen receptor}} || {{abbrlink|GR|Glucocorticoid receptor}} || {{abbrlink|MR|Mineralocorticoid receptor}} |- | Testosterone || T || 1.0 || 100 || <0.1 || 0.17 || 0.9 |- | Nandrolone || 19-NT || 20 || 154 || <0.1 || 0.5 || 1.6 |- | Trenbolone || ∆<sup>9,11</sup>-19-NT || 74 || 197 || <0.1 || 2.9 || 1.33 |- | Trestolone || 7α-Me-19-NT || 50–75 || 100–125 || ? || <1 || ? |- | Normethandrone || 17α-Me-19-NT || 100 || 146 || <0.1 || 1.5 || 0.6 |- | Metribolone || ∆<sup>9,11</sup>-17α-Me-19-NT || 208 || 204 || <0.1 || 26 || 18 |- | Mibolerone || 7α,17α-DiMe-19-NT || 214 || 108 || <0.1 || 1.4 || 2.1 |- | Dimethyltrienolone || ∆<sup>9,11</sup>-7α,17α-DiMe-19-NT || 306 || 180 || 0.1 || 22 || 52 |- class="sortbottom" | colspan="9" style="width: 1px;" | Values are percentages (%). Reference ligands (100%) were progesterone for the {{abbrlink|PR|progesterone receptor}}, testosterone for the {{abbrlink|AR|androgen receptor}}, estradiol for the {{abbrlink|ER|estrogen receptor}}, {{abbrlink|DEXA|dexamethasone}} for the {{abbrlink|GR|glucocorticoid receptor}}, and aldosterone for the {{abbrlink|MR|mineralocorticoid receptor}}. |}
==Chemistry== {{See also|List of androgens/anabolic steroids}}
Mibolerone, also known as 7α,17α-dimethyl-19-nortestosterone (DMNT) or as 7α,17α-dimethylestr-4-en-17β-ol-3-one,<ref name="pmid9228646">{{cite journal | vauthors = Markiewicz L, Gurpide E | title = Estrogenic and progestagenic activities of physiologic and synthetic androgens, as measured by in vitro bioassays | journal = Methods Find Exp Clin Pharmacol | volume = 19 | issue = 4 | pages = 215–22 | year = 1997 | pmid = 9228646 }}</ref> is a synthetic estrane steroid and a 17α-alkylated derivative of nandrolone (19-nortestosterone). It is the 17α-methyl derivative of trestolone (7α-methyl-19-nortestosterone; MENT).<ref name="pmid9228646" /> Other related AAS include metribolone (17α-methyl-δ<sup>9,11</sup>-19-nortestosterone) and dimethyltrienolone (7α,17α-dimethyl-δ<sup>9,11</sup>-19-nortestosterone).
===Synthesis=== The original patented synthesis was revised:<ref>{{cite journal | vauthors=((Yang, Q.)), ((Fan, B.)), ((Tang, R.)) | journal=Journal of Central South University of Technology | title=Synthesis and characterization of mibolerone | volume=14 | issue=4 | pages=524–527 | date= August 2007 | url=http://link.springer.com/10.1007/s11771-007-0102-4 | doi=10.1007/s11771-007-0102-4| url-access=subscription }}</ref> Precursor (also needed for Plomestane):<ref>Dai Jing & Li Lianwu, CN103601781 (2014 to Zhejiang Xianju Pharmaceutical Co Ltd).</ref> class=skin-invert-image|center|650px| The reaction of Bolandione [734-32-7] ('''1''') with triethyl orthoformate gave 3-Ethoxyestra-3,5-dien-17-one [2863-88-9] ('''2''') in 64% yield. Organometallic reaction with methyl lithium followed by hydrolysis of the dienol ether gave Normethandrone [514-61-4] ('''5''') in 40% yield. In an alternative synthesis, reaction of Estr-5(10)-ene-3,17-dione [3962-66-1] ('''3''') with methanol catalyzed by malonic acid gave a near quantitivate yield of the ketal, 3,3-dimethoxyestr-5(10)-en-17-one [19257-34-2] ('''4'''). Reaction with the organometallic reagent and hydrolysis in this case afforded a much higher yield of product (86.7%) than in the first case. Oxidation with chloranil afforded a 75.6% yield of 17-methyl-6-dehydronandrolone ('''6'''). Conjugate addition of methyl lithium in the presence of cuprous iodide (c.f. Gillman reagent) gave a 72.5% yield of mibolerone ('''7'''). [[File:Miboleronesynthesis.svg|class=skin-invert-image|651px|thumb|center|Original patented method:<ref>{{Cite patent|country=BE|number=610385}}; J. C. Babcock, J. A. Campbell, {{US patent|3341557}} (1962, 1967 both to Upjohn).</ref>]] In the other synthesis heating nandrolone acetate [1425-10-1] ('''1''') with chloranil gives 6-Dehydronandrolone Acetate [2590-41-2] ('''2'''), and reaction of that compound with methylmagnesium bromide in the presence of cuprous chloride gives (after saponification), Trestolone (7alpha-Methylnandrolone) [3764-87-2] ('''3'''). The alcohol at C17 is then oxidized to a ketone, Mentabolan [17000-78-1] ('''4'''). Enamines are commonly used to activate adjacent functions; they are also not infrequently used, as in this case, as protecting groups. Thus, reaction of the intermediate with pyrrolidine gives dienamine PC135056261 ('''5'''). This transformation emphasizes the clear difference in reactivity between ketones at C7 and C17. A second methyl Grignard addition gives the corresponding 17α-methyl derivative. Hydrolysis of the enamine function then affords mibolerone ('''6''').
For SAR purposes compare for bolasterone and calusterone.
==History== Mibolerone was first synthesized in 1963.<ref name="pmid8674183">{{cite journal | vauthors = Schänzer W | title = Metabolism of anabolic androgenic steroids | journal = Clin. Chem. | volume = 42 | issue = 7 | pages = 1001–20 | year = 1996 | pmid = 8674183 | doi = 10.1093/clinchem/42.7.1001| doi-access = free }}</ref><ref name="Llewellyn2011" />
==Society and culture==
===Generic names=== ''Mibolerone'' 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}}.<ref name="Elks2014" /><ref name="IndexNominum2000" /> It is also known as ''dimethylnortestosterone'' (''DMNT'') and by its former developmental code name ''U-10997''.<ref name="Elks2014" /><ref name="IndexNominum2000" />
===Brand names=== Mibolerone has been marketed under the brand names Cheque Drops and Matenon.<ref name="IndexNominum2000" /><ref name="Elks2014" /><ref name="Llewellyn2011" />
==References== {{Reflist}}
==External links== * [https://anabolic.org/cheque-drops-mibolerone/ Cheque Drops (mibolerone) - William Llewellyn's Anabolic.org] {{Webarchive|url=https://web.archive.org/web/20160726100040/http://anabolic.org/cheque-drops-mibolerone/ |date=2016-07-26 }}
{{Androgens and antiandrogens}} {{Progestogens and antiprogestogens}} {{Androgen receptor modulators}} {{Progesterone receptor modulators}}
Category:Abandoned drugs Category:Tertiary alcohols Category:Androgens Category:Estranes Category:Hepatotoxins Category:Enones Category:Progestogens