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Chemical compound
EM-5854
Other names 4-Fluoro-17β-hydroxy-17α-[(1-oxidopyridin-1-ium-4-yl)methyl]estra-1,3,5(10)-triene-3-carbonitrile
Drug class
Steroidal antiandrogen
(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
Formula C 25 H 27 F N 2 O 2
Molar mass 406.501 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
RBA Tooltip 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
Bica Tooltip Bicalutamide
Flu Tooltip Flutamide
OH‑Flu Tooltip Hydroxyflutamide
Enza Tooltip Enzalutamide
EM‑5854
EM‑5855
AR Tooltip Androgen receptor
RBA Tooltip relative binding affinity (%)
Human
0.18
NA
0.17
0.07
0.66
17
Metri Tooltip Metribolone = 100%
Rat
0.13
NA
0.07
0.02
0.35
2.6
Shionogi cells
AA Tooltip antiandrogenic activity
Ki (nM)
81
NA
NA
170
2.0
0.77
LNCaP cells (
PSA Tooltip 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
ER Tooltip Estrogen receptor
RBA Tooltip relative binding affinity (%)
Rat (
E2 = 100%)
0
NA
0
0
0
0
PR Tooltip Progesterone receptor
RBA Tooltip relative binding affinity (%)
Rat (
Prom Tooltip Promegestone = 100%)
ND
NA
0
ND
0.2
ND
GR Tooltip Glucocorticoid receptor
RBA Tooltip relative binding affinity (%)
Rat (
Dexa Tooltip Dexamethasone = 100%)
0
NA
0
<0.1
0
0
References
^
a
b
"EM 5854 - AdisInsight" .
^
a
b Endorecherche, Inc. Preparation of 17α-substituted steroids as systemic antiandrogens and selective androgen receptor modulators. WO2008124922; 2008
https://patents.google.com/patent/US9284345B2/en
^ 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 .
^
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 .
^
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 .
^ 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 .
^ 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 .
External links
AR Tooltip Androgen receptor
Agonists
SARMs Tooltip Selective androgen receptor modulator Antagonists
GPRC6A