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{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| Verifiedfields = changed
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| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = Investigational
| legal_status =
| routes_of_administration = [[Intravenous injection]]
| routes_of_administration = [[Intravenous injection]]


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| metabolism =
| metabolism =
| elimination_half-life =
| elimination_half-life =
| excretion =
| excretion =


<!--Identifiers-->
<!--Identifiers-->
| IUPHAR_ligand = 4919
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 185955-34-4
| CAS_number = 185955-34-4
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| ATC_supplemental =
| ATC_supplemental =
| PubChem = 6912404
| PubChem = 6912404
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank =
| DrugBank = DB04933
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = 551541VI0Y
| UNII = 551541VI0Y
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 501259
| ChEMBL = 501259
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 5288721
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = DG01426
| synonyms = E 5564
| synonyms = E 5564


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| chemical_formula =
| chemical_formula =
| C=66 | H=126 | N=2 | O=19 | P=2
| C=66 | H=126 | N=2 | O=19 | P=2
| molecular_weight = 1313.656 g/mol
| smiles = CCCCCCCCCCCC(=O)CC(=O)NC1C(C(C(OC1OP(=O)(O)O)COC2C(C(C(C(O2)COC)OP(=O)(O)O)OCCC(CCCCCCC)OC)NC(=O)CCCCCCCCCC=CCCCCCC)O)OCCCCCCCCCC
| smiles = CCCCCCCCCCCC(=O)CC(=O)NC1C(C(C(OC1OP(=O)(O)O)COC2C(C(C(C(O2)COC)OP(=O)(O)O)OCCC(CCCCCCC)OC)NC(=O)CCCCCCCCCC=CCCCCCC)O)OCCCCCCCCCC
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
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}}
}}


'''Eritoran''' is a synthetic [[lipid]] that [[Antagonist (pharmacology)|inhibits]] the [[Receptor (biochemistry)|receptor]] [[Toll-like receptor 4|TLR4]]. It was [[drug development|developed]] as a potential treatment for severe [[sepsis]], an excessive [[inflammatory response]] to an [[infection]]. It failed a five year [[Phases_of_clinical_research#Phase_III|Phase III]] clinical trial, the results of which were published in 2013,<ref name=Chen>{{cite journal | vauthors = Chen F, Zou L, Williams B, Chao W | title = Targeting Toll-Like Receptors in Sepsis: From Bench to Clinical Trials | journal = Antioxidants & Redox Signaling | volume = 35 | issue = 15 | pages = 1324–1339 | date = November 2021 | pmid = 33588628 | pmc = 8817700 | doi = 10.1089/ars.2021.0005 }}</ref><ref>{{cite journal | vauthors = Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, Wittebole X, Dugernier T, Perrotin D, Tidswell M, Jauregui L, Krell K, Pachl J, Takahashi T, Peckelsen C, Cordasco E, Chang CS, Oeyen S, Aikawa N, Maruyama T, Schein R, Kalil AC, Van Nuffelen M, Lynn M, Rossignol DP, Gogate J, Roberts MB, Wheeler JL, Vincent JL | display-authors = 6 | title = Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial | journal = JAMA | volume = 309 | issue = 11 | pages = 1154–1162 | date = March 2013 | pmid = 23512062 | doi = 10.1001/jama.2013.2194 | hdl-access = free | hdl = 1854/LU-4222072 }}</ref> and as of 2014 was no longer being developed.<ref name=Fink>{{cite journal | vauthors = Fink MP, Warren HS | title = Strategies to improve drug development for sepsis | journal = Nature Reviews. Drug Discovery | volume = 13 | issue = 10 | pages = 741–758 | date = October 2014 | pmid = 25190187 | doi = 10.1038/nrd4368 | s2cid = 20904332 }}{{Open access}}</ref>
'''Eritoran''' is an investigational drug for the treatment of severe [[sepsis]], an excessive [[inflammatory response]] to an [[infection]]. It is being developed by the Japanese pharmaceutical company [[Eisai Co.]] and administered intravenously as the [[sodium]] [[salt (chemistry)|salt]] '''eritoran tetrasodium'''.<ref>{{cite news|url=http://www.medinewsdirect.com/?p=303|title=Eritoran: A Potential Therapeutic Agent In Severe Sepsis|date=17 October 2007|publisher=MediNEWS.Direct|accessdate=26 December 2009}}</ref><ref name="PZonline">{{cite web|last=Kiemer|first=Alexandra K.|date=2008|title=TLR eröffnen neue Möglichkeiten|work=Pharmazeutische Zeitung online|publisher=Govi-Verlag|language=German|url=http://www.pharmazeutische-zeitung.de/index.php?id=4546|accessdate=26 December 2009}}</ref>


It was being developed by the Japanese pharmaceutical company [[Eisai Co.]] and was administered intravenously as the [[sodium]] [[salt (chemistry)|salt]] '''eritoran tetrasodium'''.<ref name=Barochia>{{cite journal | vauthors = Barochia A, Solomon S, Cui X, Natanson C, Eichacker PQ | title = Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 7 | issue = 4 | pages = 479–494 | date = April 2011 | pmid = 21323610 | pmc = 3065179 | doi = 10.1517/17425255.2011.558190 }}</ref>
In a phase III clinical trial,<ref>{{ClinicalTrialsGov|NCT00334828|ACCESS: A Controlled Comparison of Eritoran Tetrasodium and Placebo in Patients With Severe Sepsis}}</ref> eritoran did not perform better than existing treatments for the treatment of sepsis.<ref>{{cite journal | doi = 10.1001/jama.2013.2194}}</ref><ref>{{cite web | title = Phase III Study for Eritoran Does Not Meet Primary Endpoint | url = http://www.drugs.com/clinical_trials/phase-iii-study-eritoran-does-not-meet-primary-endpoint-11082.html | publisher = [[drugs.com]]}}</ref>


TLR4 is part of the [[innate immune system]] and plays an important role in triggering defense against [[pathogens]]. Eritoran is similar in structure to the lipopolysaccharide [[lipid A]] - a part of bacteria that binds to TLR4 and activates TLR4, triggering a defense. Eritoran binds to TLR4 but blocks its activation.<ref name=Chen/><ref name=Barochia/>
==Mechanism of action==
[[Toll-like receptor]]s (TLRs) play an important role in the [[innate immune system]]. They recognise [[microbe]]s and activate inflammatory immune responses. [[Toll-like receptor 4]] (TLR4) detects [[lipopolysaccharide]]s found in most [[Gram-negative]] bacteria.<ref>{{cite web | title = Entrez Gene: TLR4 toll-like receptor 4| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7099| accessdate = }}</ref>

Because of its similarity to the lipopolysaccharide [[lipid A]], eritoran acts as TLR4 [[receptor antagonist|antagonist]] and so blocks the excessive reaction triggered by this receptor.<ref name="PZonline" /><ref>{{cite journal|pmid=19661804|year=2010|last1=Tidswell|first1=M|last2=Tillis|first2=W|last3=Larosa|first3=SP|last4=Lynn|first4=M|last5=Wittek|first5=AE|last6=Kao|first6=R|last7=Wheeler|first7=J|last8=Gogate|first8=J|last9=Opal|first9=SM|title=Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis|volume=38|issue=1|pages=72–83|doi=10.1097/CCM.0b013e3181b07b78|journal=Critical Care Medicine}}</ref>


{| border="0"
{| border="0"
| style="vertical-align:top" | [[File:Lipid A.png|thumb|left|[[Lipid A]] as found in ''[[E. coli]]'', a gram-negative bacterium]]
| style="vertical-align:top" | [[File:Lipid A.png|thumb|left|[[Lipid A]] as found in ''[[E. coli]]'', a gram-negative bacterium<ref name=Barochia/> ]]
| style="vertical-align:top" | [[File:Eritoran acid skeletal.svg|thumb|left|Eritoran]]
| style="vertical-align:top" | [[File:Eritoran acid skeletal.svg|thumb|left|Eritoran<ref name=Barochia/> ]]
|}
|}


Too much signalling by TLR4 may be part of what causes [[cytokine storm]]s and sepsis, but as of 2021 no drug that inhibits TLR4 has been shown to prevent or treat sepsis or cytokine storms in humans.<ref name=Chen/>
==Cytokine storm==
While eritoran did not perform well in the treatment of sepsis, it was shown to combat another, related phenomenon called [[cytokine storm]] in influenza cases involving certain virus strains (involving preliminary experimentation on mice, not in other animals or humans, led by a [[University of Maryland School of Medicine]] researcher). A cytokine storm can help to cause sepsis and can in concert with it or by itself cause serious illness or death if not soon controlled. Mortality rates for sepsis, cytokine storm, and especially [[septic shock]] and organ dysfunction are still quite high despite progress made. This is in no small part due to the [[prevalence]] of [[nosocomial]] (hospital-acquired) infections, as well as ongoing mutations which confer [[multi-drug resistance]] in pathological microorganisms such as bacteria and viruses (many strains of flu are resistant to the first two drugs{{clarify|date=May 2013}} and some are resistant to [[oseltamivir]]), and delays and mistakes in the recognition and treatment of disease.<ref>{{Cite web | url = http://vitals.nbcnews.com/_news/2013/05/01/18002315-new-drug-offers-novel-approach-to-taming-flu-virus | title = New drug offers novel approach to taming flu virus | publisher = NBC News | date= 1 May 2013}}</ref> New flu strains, such as the [[H7N9]] strain, are always emerging.


==References==
== References ==
{{reflist|2}}
{{reflist|2}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Tidswell M, Tillis W, Larosa SP, Lynn M, Wittek AE, Kao R, Wheeler J, Gogate J, Opal SM | display-authors = 6 | title = Phase 2 trial of eritoran tetrasodium (E5564), a toll-like receptor 4 antagonist, in patients with severe sepsis | journal = Critical Care Medicine | volume = 38 | issue = 1 | pages = 72–83 | date = January 2010 | pmid = 19661804 | doi = 10.1097/CCM.0b013e3181b07b78 | s2cid = 19160973 }}
* {{cite journal | vauthors = Shirey KA, Lai W, Scott AJ, Lipsky M, Mistry P, Pletneva LM, Karp CL, McAlees J, Gioannini TL, Weiss J, Chen WH, Ernst RK, Rossignol DP, Gusovsky F, Blanco JC, Vogel SN | display-authors = 6 | title = The TLR4 antagonist Eritoran protects mice from lethal influenza infection | journal = Nature | volume = 497 | issue = 7450 | pages = 498–502 | date = May 2013 | pmid = 23636320 | pmc = 3725830 | doi = 10.1038/nature12118 | bibcode = 2013Natur.497..498S }}
{{refend}}


[[Category:Immunosuppressants]]
[[Category:Immunosuppressants]]

Latest revision as of 17:55, 4 November 2023

Eritoran
Clinical data
Other namesE 5564
Routes of
administration		Intravenous injection
ATC code
  • none
Identifiers
  • [(2R,3R,4R,5S,6R)-4-Decoxy-5-hydroxy-6-[[(2R,3R,4R,5S,6R)-4-[(3R)-3-methoxydecoxy]-6-(methoxymethyl)-3-[[(Z)-octadec-11-enoyl]amino]-5-phosphonatooxyoxan-2-yl]oxymethyl]-3-(3-oxotetradecanoylamino)oxan-2-yl] phosphoric acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC66H126N2O19P2
Molar mass1313.677 g·mol−1
3D model (JSmol)
  • CCCCCCCCCCCC(=O)CC(=O)NC1C(C(C(OC1OP(=O)(O)O)COC2C(C(C(C(O2)COC)OP(=O)(O)O)OCCC(CCCCCCC)OC)NC(=O)CCCCCCCCCC=CCCCCCC)O)OCCCCCCCCCC
  • InChI=1S/C66H126N2O19P2/c1-7-11-15-19-22-25-26-27-28-29-30-32-34-38-42-46-57(70)67-60-64(82-49-47-54(80-6)45-41-36-18-14-10-4)62(86-88(73,74)75)56(51-79-5)85-65(60)83-52-55-61(72)63(81-48-43-39-35-24-21-17-13-9-3)59(66(84-55)87-89(76,77)78)68-58(71)50-53(69)44-40-37-33-31-23-20-16-12-8-2/h25-26,54-56,59-66,72H,7-24,27-52H2,1-6H3,(H,67,70)(H,68,71)(H2,73,74,75)(H2,76,77,78)/b26-25-/t54-,55-,56-,59-,60-,61-,62-,63-,64-,65-,66-/m1/s1 ☒N
  • Key:BPSMYQFMCXXNPC-MFCPCZTFSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Eritoran is a synthetic lipid that inhibits the receptor TLR4. It was developed as a potential treatment for severe sepsis, an excessive inflammatory response to an infection. It failed a five year Phase III clinical trial, the results of which were published in 2013,[1][2] and as of 2014 was no longer being developed.[3]

It was being developed by the Japanese pharmaceutical company Eisai Co. and was administered intravenously as the sodium salt eritoran tetrasodium.[4]

TLR4 is part of the innate immune system and plays an important role in triggering defense against pathogens. Eritoran is similar in structure to the lipopolysaccharide lipid A - a part of bacteria that binds to TLR4 and activates TLR4, triggering a defense. Eritoran binds to TLR4 but blocks its activation.[1][4]

Lipid A as found in E. coli, a gram-negative bacterium[4]
Eritoran[4]

Too much signalling by TLR4 may be part of what causes cytokine storms and sepsis, but as of 2021 no drug that inhibits TLR4 has been shown to prevent or treat sepsis or cytokine storms in humans.[1]

References[edit]

  1. ^ a b c Chen F, Zou L, Williams B, Chao W (November 2021). "Targeting Toll-Like Receptors in Sepsis: From Bench to Clinical Trials". Antioxidants & Redox Signaling. 35 (15): 1324–1339. doi:10.1089/ars.2021.0005. PMC 8817700. PMID 33588628.
  2. ^ Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, et al. (March 2013). "Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial". JAMA. 309 (11): 1154–1162. doi:10.1001/jama.2013.2194. hdl:1854/LU-4222072. PMID 23512062.
  3. ^ Fink MP, Warren HS (October 2014). "Strategies to improve drug development for sepsis". Nature Reviews. Drug Discovery. 13 (10): 741–758. doi:10.1038/nrd4368. PMID 25190187. S2CID 20904332.Open access icon
  4. ^ a b c d Barochia A, Solomon S, Cui X, Natanson C, Eichacker PQ (April 2011). "Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies". Expert Opinion on Drug Metabolism & Toxicology. 7 (4): 479–494. doi:10.1517/17425255.2011.558190. PMC 3065179. PMID 21323610.

Further reading[edit]

Retrieved from "https://en.wikipedia.org/w/index.php?title=Eritoran&oldid=1183499137"