| 词条 | Trimethyltrienolone | ||||||||||||||||||||||||||||||||||||
| 释义 |
| Verifiedfields = | Watchedfields = | verifiedrevid = | IUPAC_name = (8R,13S,14S,17R)-17-hydroxy-2,2,13,17-tetramethyl-6,7,8,14,15,16-hexahydro-1H-cyclopenta[a]phenanthren-3-one | image = R-2956.svg | width = 225px | tradename = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = | routes_of_administration = | class = Steroidal antiandrogen | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | CAS_number_Ref = | CAS_number = 23983-19-9 | ATC_prefix = None | ATC_suffix = | ATC_supplemental = | PubChem = 170652 | IUPHAR_ligand = | DrugBank_Ref = | DrugBank = | ChemSpiderID_Ref = | ChemSpiderID = 149197 | UNII = | KEGG = | ChEBI = | ChEMBL = | synonyms = TMT; R-2956; RU-2956; 2α,2β,17α-Trimethyltrienolone; 2α,2β,17α-Trimethyltrenbolone; 2α,2β-Dimethylmetribolone; δ9,11-2α,2β,17α-trimethyl-19-nortestosterone; 2α,2β,17α-Trimethylestra-4,9,11-trien-17β-ol-3-one; 17β-Hydroxy-2α,2β,17α-trimethylestra-4,9,11-trien-3-one | C=21 | H=28 | O=2 | molecular_weight = 312.453 g/mol | SMILES = CC1(CC2=C3C=CC4(C(C3CCC2=CC1=O)CCC4(C)O)C)C | StdInChI_Ref = | StdInChI = 1S/C21H28O2/c1-19(2)12-16-13(11-18(19)22)5-6-15-14(16)7-9-20(3)17(15)8-10-21(20,4)23/h7,9,11,15,17,23H,5-6,8,10,12H2,1-4H3/t15-,17-,20-,21+/m0/s1 | StdInChIKey_Ref = | StdInChIKey = VFKZTCQVCJGPGF-STRKUORWSA-N }}Trimethyltrienolone (TMT), also known by its developmental code name R-2956 or RU-2956, is an antiandrogen medication which was never introduced for medical use but has been used in scientific research.[1][1][3] Side effectsDue to its close relation to metribolone (methyltrienolone), it is thought that TMT may produce hepatotoxicity.[4] PharmacologyPharmacodynamicsTMT is a selective and highly potent competitive antagonist of the androgen receptor (AR) with very low intrinsic/partial androgenic activity and no estrogenic, antiestrogenic, progestogenic, or antimineralocorticoid activity.[5][6] The drug is a derivative of the extremely potent androgen/anabolic steroid metribolone (R-1881; 17α-methyltrenbolone),[2][3] and has been reported to possess only about 4-fold lower affinity for the AR in comparison.[4] In accordance, it has relatively high affinity for the AR among steroidal antiandrogens, and almost completely inhibits dihydrotestosterone (DHT) binding to the AR in vitro at a mere 10-fold molar excess.[5] The AR weak partial agonistic activity of TMT is comparable to that of cyproterone acetate.[6]
Chemistry{{See also|Steroidal antiandrogen|List of steroidal antiandrogens}}TMT, also known as 2α,2β,17α-trimethyltrienolone[11] or as δ9,11-2α,2β,17α-trimethyl-19-nortestosterone, as well as 2α,2β,17α-trimethylestra-4,9,11-trien-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone and 19-nortestosterone.[5][12][1] It is the 2α,2β,17α-trimethyl derivative of trenbolone (trienolone) and the 2α,2β-dimethyl derivative of metribolone (methyltrienolone), both of which are synthetic androgens/anabolic steroids.[12] HistoryTMT was developed by Roussel Uclaf in France and was first known as early as 1969.[13][14][12] It was one of the earliest antiandrogens to be discovered and developed, along with others such as benorterone, BOMT, cyproterone, and cyproterone acetate.[15][16][17][18][19] The drug was under investigation by Roussel Uclaf for potential medical use, but was abandoned in favor of nonsteroidal antiandrogens like flutamide and nilutamide due to their comparative advantage of a complete lack of androgenicity.[20] Roussel Uclaf subsequently developed and introduced nilutamide for medical use.[21] References1. ^1 {{cite book|author1=Martin Negwer|author2=Hans-Georg Scharnow|title=Organic-chemical drugs and their synonyms: (an international survey)|url=https://books.google.com/books?id=zmpqAAAAMAAJ|year=2001|publisher=Wiley-VCH|isbn=978-3-527-30247-5|page=2158|quote=10635 (8596) C21H28O2 23983-19-9 17β-Hydroxy-2,2,17-trimethylestra-4,9,11-trien-3-one : (17β)-17-Hydroxy-2,2,17-trimethylestra-4,9,11-trien-3-one (•) S R 2956 U Anti-androgen}} {{Androgen receptor modulators}}2. ^1 2 {{cite book|author1=V. H. T. James|author2=J. R. Pasqualini|title=Proceedings of the Fourth International Congress on Hormonal Steroids: Mexico City, September 1974|url=https://books.google.com/books?id=Iq0aAwAAQBAJ&pg=PA620|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4831-4566-2|pages=618,620|quote=R-2956 [41-43], a dimethyl derivative of an extremely potent androgen, R 1881 [44], is a powerful testosterone antagonist with very low androgenic activity.}} 3. ^{{cite journal|last1=Ostgaard|first1=K.|last2=Wibe|first2=E.|last3=Eik-Nes|first3=K. B.|title=Steroid responsiveness of the human cell line NHIK 3025|journal=European Journal of Endocrinology|volume=97|issue=4|year=1981|pages=551–558|issn=0804-4643|doi=10.1530/acta.0.0970551}} 4. ^{{cite book|author=A. F. Harms|title=Innovative Approaches in Drug Research: Proceedings of the Third Noordwijkerhout Symposium on Medicinal Chemistry, Held in the Netherlands, September 3-6, 1985|url=https://books.google.com/books?id=PwhtAAAAMAAJ|date=1 January 1986|publisher=Elsevier|isbn=978-0-444-42606-2|quote=At this stage, RU 2956 exerts a competitive effect about 4 times less marked than metribolone may be because the steric hindrance of the dimethyl group in position C-2 interferes with H-bond formation between the C-3 oxygen and the receptor protein, i.e., with the recognition step, and consequently, with the association rate.}} 5. ^{{cite journal | vauthors = Eil C, Douglass EC, Rosenburg SM, Kano-Sueoka T | title = Receptor characteristics of the rat mammary carcinoma cell line 64-24 | journal = Cancer Res. | volume = 41 | issue = 1 | pages = 42–8 | year = 1981 | pmid = 6256064 | doi = | url = }} 6. ^1 {{cite journal | vauthors = Raynaud JP, Ojasoo T | title = The design and use of sex-steroid antagonists | journal = J. Steroid Biochem. | volume = 25 | issue = 5B | pages = 811–33 | date = November 1986 | pmid = 3543501 | doi = 10.1016/0022-4731(86)90313-4 | url = }} 7. ^{{cite journal | vauthors = Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, Labrie F, Mornon JP | title = Steroid hormone receptors and pharmacology | journal = Journal of Steroid Biochemistry | volume = 12 | issue = | pages = 143–57 | date = January 1980 | pmid = 7421203 | doi = 10.1016/0022-4731(80)90264-2 }} 8. ^{{cite journal | vauthors = Ojasoo T, Raynaud JP | title = Unique steroid congeners for receptor studies | journal = Cancer Research | volume = 38 | issue = 11 Pt 2 | pages = 4186–98 | date = November 1978 | pmid = 359134 | doi = | url = http://cancerres.aacrjournals.org/content/38/11_Part_2/4186.short }} 9. ^{{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 | url = }} 10. ^{{cite journal|last1=Raynaud|first1=J.P.|last2=Ojasoo|first2=T.|last3=Bouton|first3=M.M.|last4=Philibert|first4=D.|title=Receptor Binding as a Tool in the Development of New Bioactive Steroids|year=1979|pages=169–214|doi=10.1016/B978-0-12-060308-4.50010-X|url=https://books.google.com/books?id=bhAlBQAAQBAJ&pg=PA169}} 11. ^{{cite journal|last1=Kohtz|first1=Amy S.|last2=Frye|first2=Cheryl A.|title=Dissociating Behavioral, Autonomic, and Neuroendocrine Effects of Androgen Steroids in Animal Models|volume=829|year=2012|pages=397–431|issn=1064-3745|doi=10.1007/978-1-61779-458-2_26|quote=Administration of steroidal, blocking agents such as spironolactone, cyproterone acetate, or trimethyltrienolone, or nonsteroidal, such as flutamide, bicalutamide, blocking agents, can attain this result (169–171).}} 12. ^1 2 {{cite book|author=David Brandes|title=Male Accessory Sex Organs: Structure and Function in Mammals|url=https://books.google.com/books?id=TPfM6mwJozYC&pg=PA323|date=2 December 2012|publisher=Elsevier|isbn=978-0-323-14666-1|pages=323–}} 13. ^1 {{cite book|vauthors = Hughes A, Hasan SH, Oertel GW|veditors = Voss HE,Bahner F, Neumann F, Steinbeck H, Gräf KJ, Brotherton J, Horn HJ, Wagner RK|title=Androgens II and Antiandrogens / Androgene II und Antiandrogene|url=https://books.google.com/books?id=7JPsCAAAQBAJ&pg=PA1|date=27 November 2013|publisher=Springer Science & Business Media|isbn=978-3-642-80859-3|pages=1–}} 14. ^{{cite journal | vauthors = Baulieu EE, Jung I | title = A prostatic cytosol receptor | journal = Biochem. Biophys. Res. Commun. | volume = 38 | issue = 4 | pages = 599–606 | date = February 1970 | pmid = 5443703 | doi = 10.1016/0006-291X(70)90623-6 | url = }} 15. ^1 2 {{cite journal | vauthors = Azadian-Boulanger G, Bonne C, Secchi J, Raynaud JP | title = [17beta-hydroxy-2,2,17-trimethyl-estra-4, 9,11-trien-3-one). 1. Profil endocrinien. (Antiandrogenic activity of R2956 (17beta-hydroxy-2,2,17-trimethyl-estra-4,9,11-trien-3-one). 1. Endocrine profile)] Activite anti-androgene du R 2956 | journal = Journal de Pharmacologie | volume = 5 | issue = 4 | pages = 509–520 | year = 1974 | language = French | url = http://www.popline.org/node/494155 | accessdate = 12 August 2016 | quote = R 2956 (17beta-hydroxy-2,2,17-trimethyl-estra-4,9,11-trien-3-one) was tested for antiandrogenic activity in rats (Dorfman test); in dogs; for androgenic activity in female rats (Hershberger); in male rats; for progestagenic activity in rabbits (Clauberg); for uterotrophic activity in mice (Rubin); and for antiestrogenic activity in mice (Dorfman). R 2956 significantly antagonized the hypertrophic effect of .05 mg testosterone propionate on rat seminal vesicles and ventral prostate in proportion to dose from .4-5 mg/day orally. In dogs R 2956 lowered prostate epithelial hyperplasia induced by androstanolone. R 2956 had no androgenic, estrogenic, progestational, or antiestrogenic activities and inhibited development of corpora lutea to an extent comparable with that of norethindrone.}} 16. ^Bonne, C., & Raynaud, J. (1974). Anti-androgenic Activity of R 2956 (17beta-hydroxy-2,2,17alpha-trimethyl-estra-4,9,11-trien-3-one). 2. Mechanism Of Action. Journal de Pharmacologie, 5(4), 521-532. 17. ^{{cite book|author1=Masumi Inaba|author2=Yoshitaka Inaba|title=Androgenetic Alopecia: Modern Concepts of Pathogenesis and Treatment|url=https://books.google.com/books?id=RX7dBgAAQBAJ&pg=PT531|date=14 March 2013|publisher=Springer Science & Business Media|isbn=978-4-431-67038-4|pages=531–}} 18. ^{{cite book|author=Bentham Science Publishers|title=Current Medicinal Chemistry|url=https://books.google.com/books?id=2zI4_gEr80IC&pg=PA1111|date=December 1999|publisher=Bentham Science Publishers|pages=1000–1111|quote=Several androstane derivatives have also demonstrated an antiandrogenic activity; 17a-methyl-B-nortestosterone 8 was prepared and tested in 1964 for antihormonal activity [43]. Within the next decade, several other androstane analogs were prepared and found to possess antiandrogenic activity [43, 44, 45, 46] including BOMT 9 "figure 2", R2956 10, SC9420 11, and oxendolone 12 "figure 3".}} 19. ^{{cite book|author1=J. Horsky|author2=J. Presl|title=Ovarian Function and its Disorders: Diagnosis and Therapy|url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA112|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-8195-9|pages=112–}} 20. ^1 {{cite journal|last1=Raynaud|first1=J. P.|last2=Bonne|first2=C.|last3=Moguilewsky|first3=M.|last4=Lefebvre|first4=F. A.|last5=Bélanger|first5=A.|last6=Labrie|first6=F.|title=The pure antiandrogen ru 23908 (anandron®), a candidate of choice for the combined antihormonal treatment of prostatic cancer: A review|journal=The Prostate|volume=5|issue=3|year=1984|pages=299–311|issn=0270-4137|doi=10.1002/pros.2990050307|quote=[...] flutamide but we soon abandoned the development of steroid derivatives such as RU 2956 because of inherent androgenicity [17], and focused on the nonsteroidal antiandrogens.}} 21. ^{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA2935-IA22|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=2935–}} 6 : Abandoned drugs|Alcohols|Estranes|Hepatotoxins|Ketones|Steroidal antiandrogens |
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