View source for EM-5854

{{Short description|Chemical compound}}
{{Drugbox
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| IUPAC_name = (8''R'',9''S'',13''S'',14''S'',17''R'')-4-fluoro-17-hydroxy-13-methyl-17-[(1-oxidopyridin-1-ium-4-yl)methyl]-7,8,9,11,12,14,15,16-octahydro-6''H''-cyclopenta[''a'']phenanthrene-3-carbonitrile
| image = EM-5854.svg
| width = 250px
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| class = [[Steroidal antiandrogen]]
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| PubChem = 25015772
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| synonyms = 4-Fluoro-17β-hydroxy-17α-[(1-oxidopyridin-1-ium-4-yl)methyl]estra-1,3,5(10)-triene-3-carbonitrile
<!--Chemical data-->
| C=25 | H=27 | F=1 | N=2 | O=2
| SMILES = 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
| StdInChI_Ref =
| StdInChI = 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
| StdInChIKey_Ref =
| StdInChIKey = 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]].<ref name="AdisInsight">{{Cite web | url=https://adisinsight.springer.com/drugs/800044223 | title=EM 5854 - AdisInsight}}</ref><ref name="WO2008124922">Endorecherche, Inc. Preparation of 17α-substituted steroids as systemic antiandrogens and selective androgen receptor modulators. WO2008124922; 2008 https://patents.google.com/patent/US9284345B2/en</ref><ref name="pmid19505196">{{cite journal | vauthors = Zhang X, Lanter JC, Sui Z | title = Recent advances in the development of selective androgen receptor modulators | journal = Expert Opin Ther Pat | volume = 19 | issue = 9 | pages = 1239–58 | date = September 2009 | pmid = 19505196 | doi = 10.1517/13543770902994397 | s2cid = 46186955 }}</ref><ref name="pmid22449547">{{cite journal | vauthors = Gauthier S, Martel C, Labrie F | title = Steroid derivatives as pure antagonists of the androgen receptor | journal = J. Steroid Biochem. Mol. Biol. | volume = 132 | issue = 1–2 | pages = 93–104 | date = October 2012 | pmid = 22449547 | doi = 10.1016/j.jsbmb.2012.02.006 | s2cid = 28982450 }}</ref><ref name="pmid26861003">{{cite journal | vauthors = Cabeza M, Sánchez-Márquez A, Garrido M, Silva A, Bratoeff E | title = Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases | journal = Curr. Med. Chem. | volume = 23 | issue = 8 | pages = 792–815 | date = 2016 | pmid = 26861003 | pmc = 5412001 | doi = 10.2174/0929867323666160210125642 }}</ref> It was first described in a [[patent]] in 2008, and was further characterized in 2012.<ref name="WO2008124922" /><ref name="pmid22449547" /> EM-5854 reached [[Phases of clinical research#Phase I|phase I]]/[[Phases of clinical research#Phase II|II]] [[clinical trial]]s for the treatment of prostate cancer but development was discontinued in March 2019.<ref name="AdisInsight" />
The drug acts as a [[potency (pharmacology)|potent]] and [[binding selectivity|selective]] [[competitive antagonist]] of the [[androgen receptor]] (AR).<ref name="pmid22449547" /><ref name="pmid26861003" /> Unlike other steroidal antiandrogens like [[cyproterone acetate]], but similarly to [[nonsteroidal antiandrogen]]s like [[bicalutamide]] and [[enzalutamide]], EM-5854 is a pure or [[silent antagonist]] of the AR and shows no intrinsic [[partial agonist|partial]] [[androgen]]ic activity.<ref name="pmid22449547" /> EM-5854 and its [[metabolite]] [[EM-5855]] show 3.7-fold and 94-fold higher [[affinity (pharmacology)|affinity]] for the human AR than bicalutamide (0.66% and 17% of the {{abbrlink|RBA|relative binding affinity}} of [[metribolone]], respectively, compared to 0.18% for bicalutamide).<ref name="pmid22449547" /><ref name="pmid26861003" /> They also show dramatically increased [[antiandrogen]]ic [[potency (pharmacology)|potency]] relative to bicalutamide in ''[[in vivo]]'' [[bioassay|assay]]s.<ref name="pmid22449547" /><ref name="pmid26861003" /><ref name="pmid23151898">{{cite journal | vauthors = Salvador JA, Carvalho JF, Neves MA, Silvestre SM, Leitão AJ, Silva MM, Sá e Melo ML | title = Anticancer steroids: linking natural and semi-synthetic compounds | journal = Nat Prod Rep | volume = 30 | issue = 2 | pages = 324–74 | date = February 2013 | pmid = 23151898 | doi = 10.1039/c2np20082a }}</ref> 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.<ref name="pmid22449547" /> EM-5854 and EM-5855 show little to no affinity for other [[steroid hormone receptor]]s including the [[estrogen receptor|estrogen]], [[progesterone receptor|progesterone]], and [[glucocorticoid receptor]]s.<ref name="pmid22449547" /> EM-5854 bears a [[cyano]] [[phenyl]] [[functional group|group]], the [[structural motif]] of the nonsteroidal antiandrogens.<ref name="pmid31092069">{{cite journal | vauthors = Fujii S, Kagechika H | title = Androgen receptor modulators: a review of recent patents and reports (2012-2018) | journal = Expert Opin Ther Pat | volume = 29 | issue = 6 | pages = 439–453 | date = June 2019 | pmid = 31092069 | doi = 10.1080/13543776.2019.1618831 | s2cid = 155103197 }}</ref>
{| class="wikitable center sortable mw-collapsible mw-collapsed" style="width:765px; text-align:left; margin-left:auto; margin-right:auto; border:none;"
|+ <!--class="nowrap"--> | EM-5854 and other AR antagonists at steroid hormone receptors and in AR-dependent cancer cell lines<ref name="pmid22449547" />
|-
! style="width:115px;" | Activity || style="width:115px;" | Specifics || {{abbrlink|Bica|Bicalutamide}} || {{abbrlink|Flu|Flutamide}} || {{abbrlink|OH‑Flu|Hydroxyflutamide}} || {{abbrlink|Enza|Enzalutamide}} || EM‑5854 || [[EM-5855|EM‑5855]]
|-
| style="background: #f2f2f2;" | '''{{abbrlink|AR|Androgen receptor}} {{abbrlink|RBA|relative binding affinity}} (%)''' || Human || 0.18 || {{abbr|NA|Not applicable}} || 0.17 || 0.07 || 0.66 || 17
|-
| style="background: #f2f2f2;" | &nbsp;&nbsp;'''{{abbrlink|Metri|Metribolone}} = 100%''' || Rat || 0.13 || {{abbr|NA|Not applicable}} || 0.07 || 0.02 || 0.35 || 2.6
|-
| style="background: #f2f2f2;" | '''Shionogi cells {{abbrlink|AA|antiandrogenic}} activity''' || Ki (nM) || 81 || {{abbr|NA|Not applicable}} || {{abbr|NA|Not applicable}} || 170 || 2.0 || 0.77
|-
| style="background: #f2f2f2;" rowspan="2" | '''[[LNCaP]] cells ({{abbrlink|PSA|prostate-specific antigen}}) {{abbr|AA|antiandrogenic}} activity and {{abbr|stim|stimulation}} of basal {{abbr|prolif|proliferation}}''' || [[Effective dose (pharmacology)|{{abbr|De<sub>50</sub>|Median (50%) effective dose}} (nM)]] ({{abbr|Inhib|Inhibition}} at 10{{Sup|−7}}&nbsp;M (%)) || 1750<br />(6&nbsp;±&nbsp;10) || {{abbr|NA|Not applicable}} || {{abbr|NA|Not applicable}} || 1380<br />(−20&nbsp;±&nbsp;3) || 127<br />(36&nbsp;±&nbsp;7) || 66<br />(66&nbsp;±&nbsp;1)
|-
| {{abbr|Stim|Stimulation}} at 10{{Sup|−7}}&nbsp;M (%) || 0&nbsp;±&nbsp;1 || {{abbr|NA|Not applicable}} || {{abbr|NA|Not applicable}} || 1&nbsp;±&nbsp;1 || 19&nbsp;±&nbsp;1 || 29&nbsp;±&nbsp;2
|-
| style="background: #f2f2f2;" | '''{{abbrlink|ER|Estrogen receptor}} {{abbrlink|RBA|relative binding affinity}} (%)''' || Rat ([[Estradiol (medication)|{{abbr|E2|Estradiol}}]] = 100%) || 0 || {{abbr|NA|Not applicable}} || 0 || 0 || 0 || 0
|-
| style="background: #f2f2f2;" | '''{{abbrlink|PR|Progesterone receptor}} {{abbrlink|RBA|relative binding affinity}} (%)''' || Rat ({{abbrlink|Prom|Promegestone}} = 100%) || {{abbr|ND|No data}} || {{abbr|NA|Not applicable}} || 0 || {{abbr|ND|No data}} || 0.2 || ND
|-
| style="background: #f2f2f2;" | '''{{abbrlink|GR|Glucocorticoid receptor}} {{abbrlink|RBA|relative binding affinity}} (%)''' || Rat ({{abbrlink|Dexa|Dexamethasone}} = 100%) || 0 || {{abbr|NA|Not applicable}} || 0 || <0.1 || 0 || 0
|}
==References==
{{Reflist}}
==External links==
* [https://adisinsight.springer.com/drugs/800044223 EM-5854 - AdisInsight]
* [https://adisinsight.springer.com/drugs/800030757 Research programme: androgen receptor antagonists (EM-4350, EM-5855, EM-6537) - AdisInsight]
{{Androgen receptor modulators}}
[[Category:Abandoned drugs]]
[[Category:Tertiary alcohols]]
[[Category:Estranes]]
[[Category:Experimental cancer drugs]]
[[Category:Fluoroarenes]]
[[Category:Hormonal antineoplastic drugs]]
[[Category:Nitriles]]
[[Category:Prostate cancer]]
[[Category:Pyridinium compounds]]
[[Category:Steroidal antiandrogens]]
{{Genito-urinary-drug-stub}}
{{Antineoplastic-drug-stub}}