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EM-5854

EM-5854
EM-5854.svg
Clinical data
Other names4-Fluoro-17β-hydroxy-17α-[(1-oxidopyridin-1-ium-4-yl)methyl]estra-1,3,5(10)-triene-3-carbonitrile
Drug classSteroidal antiandrogen
Identifiers
PubChem CID
Chemical and physical data
FormulaC25H27FN2O2
Molar mass406.501 g/mol g·mol−1
3D model (JSmol)

EM-5854 is a steroidal antiandrogen which is or was under development by Endoceutics, Inc. (formerly Endorecherche, Inc.) for the treatment of prostate cancer.[1][2][3][4][5] It was first described in a patent in 2008, and was further characterized in 2012.[2][4][4] The drug acts as a potent and selective competitive antagonist of the androgen receptor (AR).[4][5] Unlike other steroidal antiandrogens like cyproterone acetate, but similarly to nonsteroidal antiandrogens like bicalutamide and enzalutamide, EM-5854 is a pure or silent antagonist of the AR and shows no intrinsic partial androgenic activity.[4] EM-5854 and its metabolite EM-5855 show 3.7-fold and 94-fold higher affinity for the human AR than bicalutamide (0.66% and 17% of the RBA of metribolone, respectively, compared to 0.18% for bicalutamide).[4][5] They also show dramatically increased antiandrogenic potency relative to bicalutamide in in vivo assays.[4][5][6] On the basis of the available research, it has been said that EM-5854 may possibly have 70- to 140-fold the antiandrogenic potency of bicalutamide in humans.[4] EM-5854 and EM-5855 show little to no affinity for other steroid hormone receptors including the estrogen, progesterone, and glucocorticoid receptors.[4] As of January 2016, EM-5854 is in phase I/II clinical trials for the treatment of prostate cancer.[1]

EM-5854 and other AR antagonists at steroid hormone receptors and in AR-dependent cancer cell lines[4]
Activity Specifics Bica Flu OH‑Flu Enza EM‑5854 EM‑5855
AR RBA (%) Human 0.18 NA 0.17 0.07 0.66 17
  Metri = 100% Rat 0.13 NA 0.07 0.02 0.35 2.6
Shionogi cells AA activity Ki (nM) 81 NA NA 170 2.0 0.77
LNCaP cells (PSA) AA activity and stim of basal prolif De50 (nM) (Inhib at 10−7 M (%)) 1750
(6 ± 10)
NA NA 1380
(−20 ± 3)
127
(36 ± 7)
66
(66 ± 1)
Stim at 10−7 M (%) 0 ± 1 NA NA 1 ± 1 19 ± 1 29 ± 2
ER RBA (%) Rat (E2 = 100%) 0 NA 0 0 0 0
PR RBA (%) Rat (Prom = 100%) ND NA 0 ND 0.2 ND
GR RBA (%) Rat (Dexa = 100%) 0 NA 0 <0.1 0 0

See also

References

  1. ^ a b "EM 5854 - AdisInsight".
  2. ^ a b Endorecherche, Inc. Preparation of 17α-substituted steroids as systemic antiandrogens and selective androgen receptor modulators. WO2008124922; 2008 [patents.google.com]
  3. ^ Zhang X, Lanter JC, Sui Z (September 2009). "Recent advances in the development of selective androgen receptor modulators". Expert Opin Ther Pat. 19 (9): 1239–58. doi:10.1517/13543770902994397. PMID 19505196.
  4. ^ a b c d e f g h i j Gauthier S, Martel C, Labrie F (October 2012). "Steroid derivatives as pure antagonists of the androgen receptor". J. Steroid Biochem. Mol. Biol. 132 (1–2): 93–104. doi:10.1016/j.jsbmb.2012.02.006. PMID 22449547.
  5. ^ a b c d Cabeza M, Sánchez-Márquez A, Garrido M, Silva A, Bratoeff E (2016). "Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases". Curr. Med. Chem. 23 (8): 792–815. doi:10.2174/0929867323666160210125642. PMC 5412001. PMID 26861003.
  6. ^ Salvador JA, Carvalho JF, Neves MA, Silvestre SM, Leitão AJ, Silva MM, Sá e Melo ML (February 2013). "Anticancer steroids: linking natural and semi-synthetic compounds". Nat Prod Rep. 30 (2): 324–74. doi:10.1039/c2np20082a. PMID 23151898.

External links