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Abandoned drugs
EM-5854
Другие языки:

    EM-5854

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    EM-5854
    EM-5854.svg
    Clinical data
    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
    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
    Chemical and physical data
    Formula C25H27FN2O2
    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. It was first described in a patent in 2008, and was further characterized in 2012. EM-5854 reached phase I/II clinical trials for the treatment of prostate cancer but development was discontinued in March 2019.

    The drug acts as a potent and selective competitive antagonist of the androgen receptor (AR). 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. 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). They also show dramatically increased antiandrogenic potency relative to bicalutamide in in vivo assays. 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. EM-5854 and EM-5855 show little to no affinity for other steroid hormone receptors including the estrogen, progesterone, and glucocorticoid receptors. EM-5854 bears a cyano phenyl group, the structural motif of the nonsteroidal antiandrogens.

    EM-5854 and other AR antagonists at steroid hormone receptors and in AR-dependent cancer cell lines
    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

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