Trimethyltrienolone

Trimethyltrienolone
Identifiers
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

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

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. 1 2 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. 1 2 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.


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