EM-5854

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

EM-5854
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−1
3D model (JSmol)

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] EM-5854 bears a cyanophenyl 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]
ActivitySpecificsBicaFluOH‑FluEnzaEM‑5854EM‑5855
AR RBA (%)Human0.18NA0.170.070.6617
  Metri = 100%Rat0.13NA0.070.020.352.6
Shionogi cells AA activityKi (nM)81NANA1702.00.77
LNCaP cells (PSA) AA activity and stim of basal prolifDe50 (nM) (Inhib at 10−7 M (%))1750
(6 ± 10)		NANA1380
(−20 ± 3)		127
(36 ± 7)		66
(66 ± 1)
Stim at 10−7 M (%)0 ± 1NANA1 ± 119 ± 129 ± 2
ER RBA (%)Rat (E2 = 100%)0NA0000
PR RBA (%)Rat (Prom = 100%)NDNA0ND0.2ND
GR RBA (%)Rat (Dexa = 100%)0NA0<0.100

See also

References
  1. "EM 5854 - AdisInsight".
  2. Endorecherche, Inc. Preparation of 17α-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.
  4. 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. 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.



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