Mibolerone

Mibolerone
Clinical data
Trade namesCheque Drops, Matenon
Other namesU-10997; CDB-904; Dimethylnandrolone; Dimethylnortestosterone;[1] DMNT; 7α,17α-Dimethyl-19-nortestosterone; 7α,17α-Dimethylestr-4-en-17β-ol-3-one
AHFS/Drugs.comInternational Drug Names
Routes of
administration		By mouth
Drug classAndrogen; Anabolic steroid; Progestogen
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
MetabolismLiver
Identifiers
  • (7R,8R,9S,10R,13S,14S,17S)-17-hydroxy-7,13,17-trimethyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.020.951
Chemical and physical data
FormulaC20H30O2
Molar mass302.458 g·mol−1
3D model (JSmol)
  • 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
  • InChI=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 Y
  • Key:PTQMMNYJKCSPET-OMHQDGTGSA-N Y
  (verify)

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.[3][4][5] It was indicated specifically as an oral treatment for prevention of estrus (heat) in adult female dogs.[3]

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-δ9,11-testosterone),[6][7] although potent and significant progestogenic activity remains present.[8] 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.[9]

Relative affinities (%) of mibolerone and related steroids[10][11]
Compound Chemical name PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip 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 ∆9,11-19-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 ∆9,11-17α-Me-19-NT 208 204 <0.1 26 18
Mibolerone 7α,17α-DiMe-19-NT 214 108 <0.1 1.4 2.1
Dimethyltrienolone ∆9,11-7α,17α-DiMe-19-NT 306 180 0.1 22 52
Values are percentages (%). Reference ligands (100%) were progesterone for the PRTooltip progesterone receptor, testosterone for the ARTooltip androgen receptor, estradiol for the ERTooltip estrogen receptor, DEXATooltip dexamethasone for the GRTooltip glucocorticoid receptor, and aldosterone for the MRTooltip 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,[8] 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).[8] Other related AAS include metribolone (17α-methyl-δ9,11-19-nortestosterone) and dimethyltrienolone (7α,17α-dimethyl-δ9,11-19-nortestosterone).

Synthesis

The original patented synthesis was revised:[12] Precursor (also needed for Plomestane):[13]

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).

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.[15][5]

Society and culture

Generic names

Mibolerone is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, and BANTooltip British Approved Name.[3][4] It is also known as dimethylnortestosterone (DMNT) and by its former developmental code name U-10997.[3][4]

Brand names

Mibolerone has been marketed under the brand names Cheque Drops and Matenon.[4][3][5]

References

  1. ^ Morton IK, Hall JM (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 181–. ISBN 978-0-7514-0499-9.
  2. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-15.
  3. ^ a b c d e Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 822–. ISBN 978-1-4757-2085-3.
  4. ^ a b c d Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 689–. ISBN 978-3-88763-075-1.
  5. ^ a b c William Llewellyn (2011). Anabolics. Molecular Nutrition Llc. pp. 395–. ISBN 978-0-9828280-1-4.
  6. ^ Murthy LR, Johnson MP, Rowley DR, Young CY, Scardino PT, Tindall DJ (1986). "Characterization of steroid receptors in human prostate using mibolerone". Prostate. 8 (3): 241–53. doi:10.1002/pros.2990080305. PMID 2422638. S2CID 43768386.
  7. ^ Schilling K, Liao S (1984). "The use of radioactive 7 alpha, 17 alpha-dimethyl-19-nortestosterone (mibolerone) in the assay of androgen receptors". Prostate. 5 (6): 581–8. doi:10.1002/pros.2990050603. PMID 6333679. S2CID 86370224.
  8. ^ a b c Markiewicz L, Gurpide E (1997). "Estrogenic and progestagenic activities of physiologic and synthetic androgens, as measured by in vitro bioassays". Methods Find Exp Clin Pharmacol. 19 (4): 215–22. PMID 9228646.
  9. ^ Loughney DA, Schwender CF (1992). "A comparison of progestin and androgen receptor binding using the CoMFA technique". J. Comput.-Aided Mol. Des. 6 (6): 569–81. Bibcode:1992JCAMD...6..569L. doi:10.1007/bf00126215. PMID 1291626. S2CID 22004130.
  10. ^ 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.
  11. ^ Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP (1987). "Towards the mapping of the progesterone and androgen receptors". J. Steroid Biochem. 27 (1–3): 255–69. doi:10.1016/0022-4731(87)90317-7. PMID 3695484.
  12. ^ Yang, Q., Fan, B., Tang, R. (August 2007). "Synthesis and characterization of mibolerone". Journal of Central South University of Technology. 14 (4): 524–527. doi:10.1007/s11771-007-0102-4.
  13. ^ Dai Jing & Li Lianwu, CN103601781 (2014 to Zhejiang Xianju Pharmaceutical Co Ltd).
  14. ^ BE 610385 ; J. C. Babcock, J. A. Campbell, U.S. patent 3,341,557 (1962, 1967 both to Upjohn).
  15. ^ Schänzer W (1996). "Metabolism of anabolic androgenic steroids". Clin. Chem. 42 (7): 1001–20. doi:10.1093/clinchem/42.7.1001. PMID 8674183.


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