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{{Short description|Investigational antidepressant compound}}
__NOTOC__
__NOTOC__
{{Drugbox
{{Drugbox
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<!--Clinical data-->
<!--Clinical data-->
| synonyms = NRX-1074; AGN-241660; Threonyl-prolyl-2''R''-(2-benzyl)-prolyl-threonine amide
| synonyms = NRX-1074; AGN-241660; Threonyl-prolyl-2''R''-(2-benzyl)-prolyl-threonine amide
| tradename =
| tradename =
| pregnancy_AU = <!-- A, B1, B2, B3, C, D, X -->
| pregnancy_AU = <!-- A, B1, B2, B3, C, D, X -->
| pregnancy_US = <!-- A, B, C, D, X -->
| pregnancy_US = <!-- A, B, C, D, X -->
| pregnancy_category =
| pregnancy_category =
| legal_AU = <!-- Unscheduled, S2, S3, S4, S5, S6, S7, S8, S9 -->
| legal_AU = <!-- Unscheduled, S2, S3, S4, S5, S6, S7, S8, S9 -->
| legal_CA =
| legal_CA =
| legal_UK =
| legal_UK =
| legal_US = Investigational New Drug
| legal_US = Investigational New Drug
| legal_status =
| legal_status =
| routes_of_administration = [[Oral administration|By mouth]]
| routes_of_administration = [[Oral administration|By mouth]]
| class = [[NMDA receptor modulator]]


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability =
| bioavailability =
| protein_bound =
| protein_bound =
| metabolism =
| metabolism =
| elimination_half-life =
| elimination_half-life =
| excretion =
| excretion =


<!--Identifiers-->
<!--Identifiers-->
| CAS_number_Ref =
| CAS_number_Ref =
| CAS_number = 1421866-48-9
| CAS_number = 1421866-48-9
| CAS_supplemental =
| CAS_supplemental =
| ATC_prefix =
| ATC_prefix =
| ATC_suffix =
| ATC_suffix =
| UNII = TTT1F11FZB
| UNII = TTT1F11FZB
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII_Ref = {{fdacite|correct|FDA}}
| KEGG = D11299
| KEGG = D11299
| PubChem = 71249967
| PubChem = 71249967
| DrugBank_Ref =
| DrugBank_Ref =
| DrugBank =
| DrugBank =
| ChemSpiderID_Ref =
| ChemSpiderID_Ref =
| ChemSpiderID = 52085607
| ChemSpiderID = 52085607
| ChEMBL = 3545230
| ChEMBL = 3545230
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}}
}}


'''Apimostinel''' (former developmental code name '''NRX-1074''') is an [[antidepressant]], acting as a selective [[partial agonist]] of an [[allosteric site]] of the [[glycine]] site of the [[NMDA receptor]] complex, which is under investigation by [[Naurex]] and [[Allergan]] for the treatment of [[major depressive disorder]] (MDD).<ref name="MEDRS review">{{cite journal | author = Hayley S, Litteljohn D | title = Neuroplasticity and the next wave of antidepressant strategies | journal = Front Cell Neurosci | volume = 7 | pages = 218 | date = 2013 | pmid = 24312008 | pmc = 3834236 | doi = 10.3389/fncel.2013.00218 | quote = Despite the mounting evidence indicating that ketamine has rapid and robust antidepressant properties (and notwithstanding the earlier mentioned preliminary clinical data indicating that long-term, low-dose ketamine may be both tolerable and effective; e.g., Messer et al., 2010), concerns over ketamine’s psychotomimetic effects have spurred intensive efforts to develop safer and more tolerable glutamate-based antidepressants. At the vanguard of this movement are the “next generation” NMDA receptor antagonists. Included here are the aminoadamantanes, memantine and amantadine (Sani et al., 2012); the NR2B-selective antagonists, traxoprodil (CP-101,606; Preskorn et al., 2008) and MK-0657 (Ibrahim et al., 2012a); and the low-affinity NMDA channel blocker AZD6765 (Zarate et al., 2013). The NMDA receptor glycine-site functional partial agonist, GLYX-13, and its orally bioavailable and presumed more potent analog, NRX-1074, have also garnered the recent attention of researchers and clinicians (Burgdorf et al., 2013; Dolgin, 2013), as have several modulators of metabotropic glutamate receptors (e.g., the mGluR7 allosteric agonist AMN082; Bradley et al., 2012) and select α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiators (e.g., Org 26576; Nations et al., 2012).}}</ref><ref name="PRNewswire2010">{{cite web | url = http://www.prnewswire.com/news-releases/naurexs-novel-antidepressant-glyx-13-recognized-as-one-of-windhovers-top-10-neuroscience-projects-to-watch-101866728.html | author = PR Newswire | title = Naurex's Novel Antidepressant GLYX-13 Recognized as One of Windhover's Top 10 Neuroscience Projects to Watch | year = 2010}}</ref><ref name="PRNewswire2014">{{cite web | url = http://www.prnewswire.com/news-releases/naurex-reports-positive-top-line-phase-2b-results-for-novel-antidepressant-glyx-13-and-advances-nrx-1074-into-phase-2-depression-study-258089291.html | author = PR Newswire | title = Naurex Reports Positive Top-Line Phase 2b Results for Novel Antidepressant GLYX-13 and Advances NRX-1074 into Phase 2 Depression Study | year = 2014}}</ref><ref name="pmid24410564">{{cite journal |vauthors=Dang YH, Ma XC, Zhang JC, etal | title = Targeting of NMDA Receptors in the Treatment of Major Depression | journal = Curr. Pharm. Des. | volume = 20| issue = 32| pages = 5151–9|date=January 2014 | pmid = 24410564 | doi = 10.2174/1381612819666140110120435}}</ref><ref>{{Cite web|url=http://www.prnewswire.com/news-releases/allergan-successfully-completes-naurex-acquisition-300135009.html|title=Allergan Successfully Completes Naurex Acquisition|last=plc|first=Allergan|website=www.prnewswire.com|access-date=2016-11-20}}</ref> As of 2015, an [[intravenous]] formulation of apimostinel is in a [[Phases of clinical research#Phase II|phase II]] [[clinical trial]] for MDD,<ref name="PRNewswire2014" /><ref>{{cite web|title=Study of Intravenous NRX-1074 in Patients With Major Depressive Disorder|url=https://clinicaltrials.gov/ct2/show/NCT02067793|website=Clinicaltrials.gov|publisher=US National Institutes of Health|accessdate=10 December 2014}}</ref> and an oral formulation is concurrently in [[Phases of clinical research#Phase I|phase I]] trials for MDD.
'''Apimostinel''' ('''GATE-202,''' formerly '''NRX-1074''') is an investigational [[antidepressant]], acting as a novel and selective [[Receptor modulator|modulator]] of the [[NMDA receptor]].<ref name="PRNewswire2010">{{cite web | url = http://www.prnewswire.com/news-releases/naurexs-novel-antidepressant-glyx-13-recognized-as-one-of-windhovers-top-10-neuroscience-projects-to-watch-101866728.html | publisher = PR Newswire | title = Naurex's Novel Antidepressant GLYX-13 Recognized as One of Windhover's Top 10 Neuroscience Projects to Watch | date = 31 August 2010 }}</ref><ref name="Henter_2021">{{cite journal | vauthors = Henter ID, Park LT, Zarate CA | title = Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status | journal = CNS Drugs | volume = 35 | issue = 5 | pages = 527–543 | date = May 2021 | pmid = 33904154 | pmc = 8201267 | doi = 10.1007/s40263-021-00816-x }}</ref><ref>{{cite journal | vauthors = Donello JE, Banerjee P, Li YX, Guo YX, Yoshitake T, Zhang XL, Miry O, Kehr J, Stanton PK, Gross AL, Burgdorf JS, Kroes RA, Moskal JR | display-authors = 6 | title = Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects | journal = The International Journal of Neuropsychopharmacology | volume = 22 | issue = 3 | pages = 247–259 | date = March 2019 | pmid = 30544218 | pmc = 6403082 | doi = 10.1093/ijnp/pyy101 }}</ref><ref name="MEDRS review">{{cite journal | vauthors = Hayley S, Litteljohn D | title = Neuroplasticity and the next wave of antidepressant strategies | journal = Frontiers in Cellular Neuroscience | volume = 7 | pages = 218 | date = November 2013 | pmid = 24312008 | pmc = 3834236 | doi = 10.3389/fncel.2013.00218 | doi-access = free }}</ref> It is currently under development for the acute treatment of [[major depressive disorder]] (MDD) by Gate Neurosciences, and previously by [[Naurex]] and [[Allergan]].<ref name="PRNewswire2014">{{cite web | url = http://www.prnewswire.com/news-releases/naurex-reports-positive-top-line-phase-2b-results-for-novel-antidepressant-glyx-13-and-advances-nrx-1074-into-phase-2-depression-study-258089291.html | archive-url = https://web.archive.org/web/20140714112115/http://www.prnewswire.com/news-releases/naurex-reports-positive-top-line-phase-2b-results-for-novel-antidepressant-glyx-13-and-advances-nrx-1074-into-phase-2-depression-study-258089291.html | archive-date = 14 July 2014 | publisher = PR Newswire | title = Naurex Reports Positive Top-Line Phase 2b Results for Novel Antidepressant GLYX-13 and Advances NRX-1074 into Phase 2 Depression Study | date = 6 May 2014 }}</ref><ref>{{Cite press release|url=http://www.prnewswire.com/news-releases/allergan-successfully-completes-naurex-acquisition-300135009.html|title=Allergan Successfully Completes Naurex Acquisition | work = Allergan plc | publisher = PR Newswire |access-date=2016-11-20}}</ref><ref>{{Cite web |title=Home - Gate Neurosciences |url=https://www.gateneuro.com/ |access-date=2022-05-12 |language=en-US}}</ref> As of February 2015, an [[intravenous]] formulation of apimostinel has completed a [[Phases of clinical research#Phase II|phase IIa]] [[clinical trial]] for MDD.<ref name="PRNewswire2014" /><ref>{{ClinicalTrialsGov|NCT02067793|Study of Intravenous NRX-1074 in Patients With Major Depressive Disorder}}</ref>


Its [[mechanism of action]] and effects are similar to those of [[rapastinel]] (GLYX-13), which is under development as an [[adjunctive therapy]] for [[treatment-resistant depression]] also by Naurex. However, apimostinel is 100-fold more potent by weight and, whereas rapastinel must be administered via [[intravenous injection]], is orally-active.<ref name="PRNewswire2014" /> Apimostinel is intended by Naurex as an improved, follow-up drug to rapastinel. Similarly to rapastinel, apimostinel is an [[amide|amidated]] [[tetrapeptide]], and has almost an identical [[chemical structure]] to rapastinel, but has been [[molecular modification|structurally modified]] via the addition of a [[benzyl group]]. The drug has shown rapid [[antidepressant]] effects in [[animal model|pre-clinical model]]s of [[depression (mood)|depression]].<ref name="PRNewswire2014" /> In addition, similarly to rapastinel, it is well tolerated and lacks the [[schizophrenia]]-like [[psychotomimetic]] effects of other [[NMDA receptor antagonist]]s such as [[ketamine]].<ref name="PRNewswire2014" />
Similar to [[rapastinel]] (GLYX-13), its [[mechanism of action]] acts through a unique binding site on the NMDA receptor, independent of the glycine site, to modulate receptor activity and enhance NMDAR-mediated synaptic plasticity.<ref>{{cite journal | vauthors = Donello JE, Banerjee P, Li YX, Guo YX, Yoshitake T, Zhang XL, Miry O, Kehr J, Stanton PK, Gross AL, Burgdorf JS, Kroes RA, Moskal JR | display-authors = 6 | title = Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects | journal = The International Journal of Neuropsychopharmacology | volume = 22 | issue = 3 | pages = 247–259 | date = March 2019 | pmid = 30544218 | pmc = 6403082 | doi = 10.1093/ijnp/pyy101 }}</ref> However, apimostinel is 1000-fold more potent in vitro and is intended as an improved, follow-up drug to rapastinel.<ref name="Henter_2021" /><ref name="PRNewswire2014" /> Similar to rapastinel, apimostinel is an [[amide|amidated]] [[tetrapeptide]], but has been [[molecular modification|structurally modified]], via the addition of a [[benzyl group]], to enhance its metabolic stability and pharmacokinetic profile. The drug has shown rapid and potent [[antidepressant]] effects in [[animal model|pre-clinical model]]s of [[depression (mood)|depression]].<ref name="PRNewswire2014" /> In addition, similarly to rapastinel, it is well tolerated and lacks the [[schizophrenia]]-like [[psychotomimetic]] effects of [[NMDA receptor antagonist]]s such as [[ketamine]].<ref name="PRNewswire2014" />


⚫
== See also ==
Commercial competitors of apimostinel include [[4-chlorokynurenine|AV-101]] from VistaGen Therapeutics and Cerecor's [[CERC-301]].<sup>[[CERC-301#cite note-8|[8]]]</sup>

⚫
==See also==
* [[List of investigational antidepressants]]
* [[List of investigational antidepressants]]
* [[Sarcosine]]
* [[AGN-241751|Zelquistinel]]


==References==
== References ==
{{Reflist|2}}
{{Reflist|2}}


==External links==
== External links ==
* [http://adisinsight.springer.com/drugs/800038114 Apimostinel (NRX-1074) - AdisInsight]
* [http://adisinsight.springer.com/drugs/800038114 Apimostinel (NRX-1074) - AdisInsight]


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{{Ionotropic glutamate receptor modulators}}
{{Ionotropic glutamate receptor modulators}}


[[Category:Antidepressants]]
[[Category:Benzyl compounds]]
[[Category:Benzyl compounds]]
[[Category:Carboxamides]]
[[Category:Carboxamides]]
[[Category:Experimental drugs]]
[[Category:Experimental antidepressants]]
[[Category:NMDA receptor agonists]]
[[Category:NMDA receptor agonists]]
[[Category:Peptides]]
[[Category:Tetrapeptides]]
[[Category:Pyrrolidines]]
[[Category:Pyrrolidines]]

Latest revision as of 19:08, 25 January 2024

Apimostinel
Clinical data
Other namesNRX-1074; AGN-241660; Threonyl-prolyl-2R-(2-benzyl)-prolyl-threonine amide
Routes of
administration		By mouth
Drug classNMDA receptor modulator
Legal status
Legal status
Identifiers
  • (2R)-1-[(2S)-1-[(2S,3R)-2-Amino-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]-2-benzylpyrrolidine-2-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC25H37N5O6
Molar mass503.600 g·mol−1
3D model (JSmol)
  • C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N2CCC[C@@]2(Cc3ccccc3)C(=O)N[C@@H]([C@@H](C)O)C(N)=O
  • InChI=1S/C25H37N5O6/c1-15(31)19(26)23(35)29-12-6-10-18(29)22(34)30-13-7-11-25(30,14-17-8-4-3-5-9-17)24(36)28-20(16(2)32)21(27)33/h3-5,8-9,15-16,18-20,31-32H,6-7,10-14,26H2,1-2H3,(H2,27,33)(H,28,36)/t15-,16-,18+,19+,20+,25-/m1/s1
  • Key:DVBUEXCIEIAXPM-PJUQSVSOSA-N

Apimostinel (GATE-202, formerly NRX-1074) is an investigational antidepressant, acting as a novel and selective modulator of the NMDA receptor.[1][2][3][4] It is currently under development for the acute treatment of major depressive disorder (MDD) by Gate Neurosciences, and previously by Naurex and Allergan.[5][6][7] As of February 2015, an intravenous formulation of apimostinel has completed a phase IIa clinical trial for MDD.[5][8]

Similar to rapastinel (GLYX-13), its mechanism of action acts through a unique binding site on the NMDA receptor, independent of the glycine site, to modulate receptor activity and enhance NMDAR-mediated synaptic plasticity.[9] However, apimostinel is 1000-fold more potent in vitro and is intended as an improved, follow-up drug to rapastinel.[2][5] Similar to rapastinel, apimostinel is an amidated tetrapeptide, but has been structurally modified, via the addition of a benzyl group, to enhance its metabolic stability and pharmacokinetic profile. The drug has shown rapid and potent antidepressant effects in pre-clinical models of depression.[5] In addition, similarly to rapastinel, it is well tolerated and lacks the schizophrenia-like psychotomimetic effects of NMDA receptor antagonists such as ketamine.[5]

See also

[edit]

References

[edit]
  1. ^ "Naurex's Novel Antidepressant GLYX-13 Recognized as One of Windhover's Top 10 Neuroscience Projects to Watch". PR Newswire. 31 August 2010.
  2. ^ a b Henter ID, Park LT, Zarate CA (May 2021). "Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status". CNS Drugs. 35 (5): 527–543. doi:10.1007/s40263-021-00816-x. PMC 8201267. PMID 33904154.
  3. ^ Donello JE, Banerjee P, Li YX, Guo YX, Yoshitake T, Zhang XL, et al. (March 2019). "Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects". The International Journal of Neuropsychopharmacology. 22 (3): 247–259. doi:10.1093/ijnp/pyy101. PMC 6403082. PMID 30544218.
  4. ^ Hayley S, Litteljohn D (November 2013). "Neuroplasticity and the next wave of antidepressant strategies". Frontiers in Cellular Neuroscience. 7: 218. doi:10.3389/fncel.2013.00218. PMC 3834236. PMID 24312008.
  5. ^ a b c d e "Naurex Reports Positive Top-Line Phase 2b Results for Novel Antidepressant GLYX-13 and Advances NRX-1074 into Phase 2 Depression Study". PR Newswire. 6 May 2014. Archived from the original on 14 July 2014.
  6. ^ "Allergan Successfully Completes Naurex Acquisition". Allergan plc (Press release). PR Newswire. Retrieved 2016-11-20.
  7. ^ "Home - Gate Neurosciences". Retrieved 2022-05-12.
  8. ^ Clinical trial number NCT02067793 for "Study of Intravenous NRX-1074 in Patients With Major Depressive Disorder" at ClinicalTrials.gov
  9. ^ Donello JE, Banerjee P, Li YX, Guo YX, Yoshitake T, Zhang XL, et al. (March 2019). "Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects". The International Journal of Neuropsychopharmacology. 22 (3): 247–259. doi:10.1093/ijnp/pyy101. PMC 6403082. PMID 30544218.
[edit]
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