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EM-5854

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EM-5854
Clinical data
Other names4-Fluoro-17βべーた-hydroxy-17αあるふぁ-[(1-oxidopyridin-1-ium-4-yl)methyl]estra-1,3,5(10)-triene-3-carbonitrile
Drug classSteroidal antiandrogen
Identifiers
  • (8R,9S,13S,14S,17R)-4-fluoro-17-hydroxy-13-methyl-17-[(1-oxidopyridin-1-ium-4-yl)methyl]-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3-carbonitrile
PubChem CID
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC25H27FN2O2
Molar mass406.501 g·mol−1
3D model (JSmol)
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(CC4=CC=[N+](C=C4)[O-])O)CCC5=C3C=CC(=C5F)C#N
  • InChI=1S/C25H27FN2O2/c1-24-10-6-19-18-3-2-17(15-27)23(26)21(18)5-4-20(19)22(24)7-11-25(24,29)14-16-8-12-28(30)13-9-16/h2-3,8-9,12-13,19-20,22,29H,4-7,10-11,14H2,1H3/t19-,20-,22+,24+,25-/m1/s1
  • Key:YKLVHERADAJQQV-NGQKKBAQSA-N

EM-5854 is a steroidal antiandrogen which 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] EM-5854 reached phase I/II clinical trials for the treatment of prostate cancer but development was discontinued in March 2019.[1]

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 RBATooltip relative binding affinity 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] EM-5854 bears a cyano phenyl group, the structural motif of the nonsteroidal antiandrogens.[7]

EM-5854 and other AR antagonists at steroid hormone receptors and in AR-dependent cancer cell lines[4]
Activity Specifics BicaTooltip Bicalutamide FluTooltip Flutamide OH‑FluTooltip Hydroxyflutamide EnzaTooltip Enzalutamide EM‑5854 EM‑5855
ARTooltip Androgen receptor RBATooltip relative binding affinity (%) Human 0.18 NA 0.17 0.07 0.66 17
  MetriTooltip Metribolone = 100% Rat 0.13 NA 0.07 0.02 0.35 2.6
Shionogi cells AATooltip antiandrogenic activity Ki (nM) 81 NA NA 170 2.0 0.77
LNCaP cells (PSATooltip prostate-specific antigen) 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
ERTooltip Estrogen receptor RBATooltip relative binding affinity (%) Rat (E2 = 100%) 0 NA 0 0 0 0
PRTooltip Progesterone receptor RBATooltip relative binding affinity (%) Rat (PromTooltip Promegestone = 100%) ND NA 0 ND 0.2 ND
GRTooltip Glucocorticoid receptor RBATooltip relative binding affinity (%) Rat (DexaTooltip Dexamethasone = 100%) 0 NA 0 <0.1 0 0

References

[edit]
  1. ^ a b "EM 5854 - AdisInsight".
  2. ^ a b Endorecherche, Inc. Preparation of 17αあるふぁ-substituted steroids as systemic antiandrogens and selective androgen receptor modulators. WO2008124922; 2008 https://patents.google.com/patent/US9284345B2/en
  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. S2CID 46186955.
  4. ^ a b c d e f g h i 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. S2CID 28982450.
  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.
  7. ^ Fujii S, Kagechika H (June 2019). "Androgen receptor modulators: a review of recent patents and reports (2012-2018)". Expert Opin Ther Pat. 29 (6): 439–453. doi:10.1080/13543776.2019.1618831. PMID 31092069. S2CID 155103197.
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