Trimethyltrienolone

Trimethyltrienolone

Identifiers
IUPAC name (10R,11S,14R,15S)-14-hydroxy-4,4,14,15-tetramethyltetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadeca-1,6,16-trien-5-one
Synonyms	R-2956; RU-2956; 2α,2β,17α-Trimethyltrienolone; 2α,2β-Dimethylmetribolone; 17β-Hydroxy-2α,2β,17α-trimethylestra-4,9,11-trien-3-one
CAS Number	42438-88-0 23983-19-9 (17β-isomer)
PubChem (CID)	170652
ChemSpider	149197
Chemical and physical data
Formula	C21H28O2
Molar mass	312.45 g·mol^−1
3D model (Jmol)	Interactive image
SMILES CC1(CC2=C3C=CC4(C(C3CCC2=CC1=O)CCC4(C)O)C)C
InChI InChI=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 Key:VFKZTCQVCJGPGF-STRKUORWSA-N

Trimethyltrienolone (developmental code name R-2956 or RU-2956), or 2α,2β,17α-trimethyltrenbolone,^[1] also known as 2α,2β,17α-trimethylestra-4,9,11-trien-17β-ol-3-one, is a steroidal antiandrogen derived from testosterone that was first described in 1973^[2] and was one of the earliest antiandrogens to be discovered and developed.^[3][4][5][6] It is a derivative of the extremely potent androgenic-anabolic steroid metribolone (R-1881; 17α-methyltrenbolone),^[7][8] and possesses only about 4-fold lower competitive affinity for the androgen receptor (AR) in comparison.^[9] Trimethyltrienolone is a powerful and selective antagonist of the androgen receptor (AR) with very low intrinsic androgenic activity and no estrogenic, antiestrogenic, or progestogenic activity.^[3][7] The drug almost completely inhibits dihydrotestosterone (DHT) binding to the AR in vitro at a mere 10-fold molar excess.^[10] It was under investigation for potential clinical use, but was abandoned in favor of non-steroidal antiandrogens like flutamide and nilutamide due to their comparative advantage of a complete lack of androgenicity, and hence, was never marketed.^[11]

See also

• Benorterone
• BOMT
• Chlormadinone acetate
• Cyproterone acetate
• Megestrol acetate
• Spironolactone

References

1. Kohtz, Amy S.; Frye, Cheryl A. (2012). "Dissociating Behavioral, Autonomic, and Neuroendocrine Effects of Androgen Steroids in Animal Models". 829: 397–431. doi:10.1007/978-1-61779-458-2_26. ISSN 1064-3745. 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).
2. Sufrin G, Coffey DS (1973). "A new model for studying the effect of drugs on prostatic growth. 1. Antiandrogens and DNA synthesis". Invest Urol. 11 (1): 45–54. PMID 4724272.
3. Azadian-Boulanger G, Bonne C, Secchi J, Raynaud JP (1974). "[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 de Pharmacologie (in French). 5 (4): 509–520. Retrieved 12 August 2016. 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.
4. Masumi Inaba; Yoshitaka Inaba (14 March 2013). Androgenetic Alopecia: Modern Concepts of Pathogenesis and Treatment. Springer Science & Business Media. pp. 531–. ISBN 978-4-431-67038-4.
5. Bentham Science Publishers (December 1999). Current Medicinal Chemistry. Bentham Science Publishers. pp. 1000–1111. 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".
6. J. Horsky; J. Presl (6 December 2012). Ovarian Function and its Disorders: Diagnosis and Therapy. Springer Science & Business Media. pp. 112–. ISBN 978-94-009-8195-9.
7. V. H. T. James; J. R. Pasqualini (22 October 2013). Proceedings of the Fourth International Congress on Hormonal Steroids: Mexico City, September 1974. Elsevier Science. p. 618. ISBN 978-1-4831-4566-2. 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.
8. Ostgaard, K.; Wibe, E.; Eik-Nes, K. B. (1981). "Steroid responsiveness of the human cell line NHIK 3025". European Journal of Endocrinology. 97 (4): 551–558. doi:10.1530/acta.0.0970551. ISSN 0804-4643.
9. A. F. Harms (1 January 1986). Innovative Approaches in Drug Research: Proceedings of the Third Noordwijkerhout Symposium on Medicinal Chemistry, Held in the Netherlands, September 3-6, 1985. Elsevier. ISBN 978-0-444-42606-2. 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.
10. Eil C, Douglass EC, Rosenburg SM, Kano-Sueoka T (1981). "Receptor characteristics of the rat mammary carcinoma cell line 64-24". Cancer Res. 41 (1): 42–8. PMID 6256064.
11. Raynaud, J. P.; Bonne, C.; Moguilewsky, M.; Lefebvre, F. A.; Bélanger, A.; Labrie, F. (1984). "The pure antiandrogen ru 23908 (anandron®), a candidate of choice for the combined antihormonal treatment of prostatic cancer: A review". The Prostate. 5 (3): 299–311. doi:10.1002/pros.2990050307. ISSN 0270-4137. [...] 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.