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Perzinfotel: Difference between revisions

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{{Short description|Chemical compound}}
{{Drugbox {{Drugbox
| Verifiedfields = changed |Verifiedfields = changed
|Watchedfields = changed
| verifiedrevid = 443223642 |verifiedrevid = 443223642
| IUPAC_name = 2-(8,9-dioxo-2,6-diazabicyclonon-1(7)-en-2-yl)ethylphosphonic acid |IUPAC_name = 2-(8,9-Dioxo-2,6-diazabicyclonon-1(7)-en-2-yl)ethylphosphonic acid
| image = Perzinfotel.png |image = Perzinfotel.svg
| width = 240 |width = 150

⚫ |CAS_number_Ref = {{cascite|correct|??}}
<!--Clinical data-->
⚫ |CAS_number = 144912-63-0
| tradename =
⚫ |ATC_prefix = none
| routes_of_administration =
⚫ |PubChem = 6918236

⚫ |DrugBank_Ref = {{drugbankcite|correct|drugbank}}
<!--Pharmacokinetic data-->
⚫ |UNII_Ref = {{fdacite|correct|FDA}}
| metabolism =
⚫ |UNII = FX5AUU7Z8T
| elimination_half-life =
⚫ |KEGG_Ref = {{keggcite|correct|kegg}}
| excretion =
⚫ |KEGG = D05447

⚫ |ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
<!--Identifiers-->
⚫ |ChemSpiderID = 5293443
⚫ | CAS_number_Ref = {{cascite|correct|??}}
⚫ |C=9 | H=13 | N=2 | O=5 | P=1
⚫ | CAS_number = 144912-63-0
⚫ |smiles = C1CNC2=C(C(=O)C2=O)N(C1)CCP(=O)(O)O
⚫ | ATC_prefix = none
⚫ |StdInChI_Ref = {{stdinchicite|changed|chemspider}}
⚫ | PubChem = 6918236
⚫ |StdInChI = 1S/C9H13N2O5P/c12-8-6-7(9(8)13)11(3-1-2-10-6)4-5-17(14,15)16/h10H,1-5H2,(H2,14,15,16)
⚫ | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
⚫ |StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
⚫ | UNII_Ref = {{fdacite|correct|FDA}}
⚫ |StdInChIKey = BDABGOLMYNHHTR-UHFFFAOYSA-N
⚫ | UNII = FX5AUU7Z8T
⚫ | KEGG_Ref = {{keggcite|correct|kegg}}
⚫ | KEGG = D05447
⚫ | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
⚫ | ChemSpiderID = 5293443

<!--Chemical data-->
⚫ | C=9 | H=13 | N=2 | O=5 | P=1
| molecular_weight = 260.184 g/mol
⚫ | smiles = C1CNC2=C(C(=O)C2=O)N(C1)CCP(=O)(O)O
| InChI = 1/C9H13N2O5P/c12-8-6-7(9(8)13)11(3-1-2-10-6)4-5-17(14,15)16/h10H,1-5H2,(H2,14,15,16)
| InChIKey = BDABGOLMYNHHTR-UHFFFAOYAC
⚫ | StdInChI_Ref = {{stdinchicite|changed|chemspider}}
⚫ | StdInChI = 1S/C9H13N2O5P/c12-8-6-7(9(8)13)11(3-1-2-10-6)4-5-17(14,15)16/h10H,1-5H2,(H2,14,15,16)
⚫ | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
⚫ | StdInChIKey = BDABGOLMYNHHTR-UHFFFAOYSA-N
}} }}
'''Perzinfotel''' ('''EAA-090''') is a drug which acts as a potent ].<ref>Kinney WA, Abou-Gharbia M, Garrison DT, Schmid J, Kowal DM, Bramlett DR, Miller TL, Tasse RP, Zaleska MM, Moyer JA. Design and synthesis of non-1(7)-en-2-yl)-ethyl]phosphonic acid (EAA-090), a potent N-methyl-D-aspartate antagonist, via the use of 3-cyclobutene-1,2-dione as an achiral alpha-amino acid bioisostere. ''Journal of Medicinal Chemistry''. 1998 Jan 15;41(2):236-46. PMID 9457246</ref> It has ] effects and has been investigated for the treatment of ],<ref>Sun L, Chiu D, Kowal D, Simon R, Smeyne M, Zukin RS, Olney J, Baudy R, Lin S. Characterization of two novel N-methyl-D-aspartate antagonists: EAA-090 (2-non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-alpha-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride). ''Journal of Pharmacology and Experimental Therapeutics''. 2004 Aug;310(2):563-70. PMID 15075380</ref> but lacks ] effects.<ref>Brandt MR, Cummons TA, Potestio L, Sukoff SJ, Rosenzweig-Lipson S. Effects of the N-methyl-D-aspartate receptor antagonist perzinfotel non-1(7)-en-2-yl)-ethyl]phosphonic acid] on chemically induced thermal hypersensitivity. ''Journal of Pharmacology and Experimental Therapeutics''. 2005 Jun;313(3):1379-86. PMID 15764736</ref> Nevertheless it shows a good safety profile compared to older drugs, and further research is ongoing. To increase the low oral ] of Perzinfotel (3-5%), ] derivatives were synthesized and evaluated.<ref>{{Cite doi|10.1021/jm8011799}}</ref> '''Perzinfotel''' ('''EAA-090''') is a drug which acts as a potent ].<ref>{{cite journal | vauthors = Kinney WA, Abou-Gharbia M, Garrison DT, Schmid J, Kowal DM, Bramlett DR, Miller TL, Tasse RP, Zaleska MM, Moyer JA | display-authors = 6 | title = Design and synthesis of non-1(7)-en-2-yl)-ethyl]phosphonic acid (EAA-090), a potent N-methyl-D-aspartate antagonist, via the use of 3-cyclobutene-1,2-dione as an achiral alpha-amino acid bioisostere | journal = Journal of Medicinal Chemistry | volume = 41 | issue = 2 | pages = 236–46 | date = January 1998 | pmid = 9457246 | doi = 10.1021/jm970504g }}</ref> It has ] effects and has been investigated for the treatment of ],<ref>{{cite journal | vauthors = Sun L, Chiu D, Kowal D, Simon R, Smeyne M, Zukin RS, Olney J, Baudy R, Lin S | title = Characterization of two novel N-methyl-D-aspartate antagonists: EAA-090 (2-non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-alpha-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride) | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 310 | issue = 2 | pages = 563–70 | date = August 2004 | pmid = 15075380 | doi = 10.1124/jpet.104.066092 | s2cid = 25505657 }}</ref> but lacks ] effects.<ref>{{cite journal | vauthors = Brandt MR, Cummons TA, Potestio L, Sukoff SJ, Rosenzweig-Lipson S | title = Effects of the N-methyl-D-aspartate receptor antagonist perzinfotel non-1(7)-en-2-yl)-ethyl]phosphonic acid] on chemically induced thermal hypersensitivity | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 313 | issue = 3 | pages = 1379–86 | date = June 2005 | pmid = 15764736 | doi = 10.1124/jpet.105.084467 | s2cid = 12989500}}</ref> Nevertheless, it shows a good safety profile compared to older drugs, although further development of this drug has been discontinued.<ref>{{cite web | title = Perzinfotel | url = http://adisinsight.springer.com/drugs/800009946 | work = Adis International Ltd. | publisher = Springer Nature Switzerland AG }}</ref>
==Background==
Pain receptors become sensitized during inflammation or from a related stimuli, and consequently often release glutamate. That amino
acid then acts on NMDA receptors on neurons, and in the process further sensitizes those to pain stimuli. This sequence then causes
the pain to become chronic. Specific NMDA antagonists would thus be expected to relieve chronic pain by interrupting that chain. Consequently, such compounds would offer a potentially nonaddictive alternative to the opiates currently used to treat chronic pain.
==Synthesis==
Reductive amination of the acetaldehyde derivative # with ]-] (#) leads to the now-disubstituted ] #. Reaction of this amine with the commercially available cyclobutenedione derivative # leads to replacement of one of the ethoxy groups in # by the free amino group in # by what is probably an addition–elimination sequence to afford the coupled product #.


Prodrugs were developed since the oral bioavailability of perzinfotel is only around 3-5%.<ref name="BaudyButera2009">{{cite journal | vauthors = Baudy RB, Butera JA, Abou-Gharbia MA, Chen H, Harrison B, Jain U, Magolda R, Sze JY, Brandt MR, Cummons TA, Kowal D, Pangalos MN, Zupan B, Hoffmann M, May M, Mugford C, Kennedy J, Childers WE | display-authors = 6 | title = Prodrugs of perzinfotel with improved oral bioavailability | journal = Journal of Medicinal Chemistry | volume = 52 | issue = 3 | pages = 771–8 | date = February 2009 | pmid = 19146418 | doi = 10.1021/jm8011799 }}</ref>
]

Reduction of this intermediate by hydrogen transfer from 1,4-cyclohexadiene in the presence of platinum leads to loss of the carbobenzoxy
group and formation of the transient primary amine #. The terminal primary amino group in that product then participates in a second
addition–elimination sequence to form an eight-membered ring (#). Treatment of this intermediate with trimethylsilyl bromide then cleaves
the ethyl ethers on phosphorus to give the free phosphonic acid and thus perzinfotel.


== References == == References ==
{{reflist}} {{reflist}}


{{Glutamatergics}}
{{Hallucinogens}} {{Hallucinogens}}
{{Ionotropic glutamate receptor modulators}}



⚫ ]
] ]
] ]
] ]
⚫ ]
]
]
]
]



{{nervous-system-drug-stub}} {{nervous-system-drug-stub}}

Latest revision as of 00:43, 18 February 2024

Chemical compound Pharmaceutical compound
Perzinfotel
Clinical data
ATC code
  • none
Identifiers
IUPAC name
  • 2-(8,9-Dioxo-2,6-diazabicyclonon-1(7)-en-2-yl)ethylphosphonic acid
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.222.780 Edit this at Wikidata
Chemical and physical data
FormulaC9H13N2O5P
Molar mass260.186 g·mol
3D model (JSmol)
SMILES
  • C1CNC2=C(C(=O)C2=O)N(C1)CCP(=O)(O)O
InChI
  • InChI=1S/C9H13N2O5P/c12-8-6-7(9(8)13)11(3-1-2-10-6)4-5-17(14,15)16/h10H,1-5H2,(H2,14,15,16)
  • Key:BDABGOLMYNHHTR-UHFFFAOYSA-N
  (what is this?)  (verify)

Perzinfotel (EAA-090) is a drug which acts as a potent NMDA antagonist. It has neuroprotective effects and has been investigated for the treatment of stroke, but lacks analgesic effects. Nevertheless, it shows a good safety profile compared to older drugs, although further development of this drug has been discontinued.

Prodrugs were developed since the oral bioavailability of perzinfotel is only around 3-5%.

References

  1. Kinney WA, Abou-Gharbia M, Garrison DT, Schmid J, Kowal DM, Bramlett DR, et al. (January 1998). "Design and synthesis of non-1(7)-en-2-yl)-ethyl]phosphonic acid (EAA-090), a potent N-methyl-D-aspartate antagonist, via the use of 3-cyclobutene-1,2-dione as an achiral alpha-amino acid bioisostere". Journal of Medicinal Chemistry. 41 (2): 236–46. doi:10.1021/jm970504g. PMID 9457246.
  2. Sun L, Chiu D, Kowal D, Simon R, Smeyne M, Zukin RS, Olney J, Baudy R, Lin S (August 2004). "Characterization of two novel N-methyl-D-aspartate antagonists: EAA-090 (2-non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-alpha-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride)". The Journal of Pharmacology and Experimental Therapeutics. 310 (2): 563–70. doi:10.1124/jpet.104.066092. PMID 15075380. S2CID 25505657.
  3. Brandt MR, Cummons TA, Potestio L, Sukoff SJ, Rosenzweig-Lipson S (June 2005). "Effects of the N-methyl-D-aspartate receptor antagonist perzinfotel non-1(7)-en-2-yl)-ethyl]phosphonic acid] on chemically induced thermal hypersensitivity". The Journal of Pharmacology and Experimental Therapeutics. 313 (3): 1379–86. doi:10.1124/jpet.105.084467. PMID 15764736. S2CID 12989500.
  4. "Perzinfotel". Adis International Ltd. Springer Nature Switzerland AG.
  5. Baudy RB, Butera JA, Abou-Gharbia MA, Chen H, Harrison B, Jain U, et al. (February 2009). "Prodrugs of perzinfotel with improved oral bioavailability". Journal of Medicinal Chemistry. 52 (3): 771–8. doi:10.1021/jm8011799. PMID 19146418.
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