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{{Short description|Investigational antidepressant compound}}
{{NOTOC}}
__NOTOC__
{{Drugbox
{{Drugbox
| Verifiedfields =
| Verifiedfields =
| Watchedfields =
| Watchedfields =
| verifiedrevid =
| verifiedrevid =
| IUPAC_name = (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
| IUPAC_name = (2''R'')-1-[(2''S'')-1-[(2''S'',3''R'')-2-Amino-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]-''N''-[(2''S'',3''R'')-1-amino-3-hydroxy-1-oxobutan-2-yl]-2-benzylpyrrolidine-2-carboxamide
| image = NRX-1074.svg
| image = NRX-1074.svg
| width = 250
| width = 250px


<!--Clinical data-->
<!--Clinical data-->
| synonyms = NRX-1074, AGN-241660, Threonyl-prolyl-2R-(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 -->
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| legal_UK =
| legal_UK =
| legal_US = Investigational New Drug
| legal_US = Investigational New Drug
| legal_status =
| legal_status =
| routes_of_administration =
| routes_of_administration = [[Oral administration|By mouth]]
| class = [[NMDA receptor modulator]]


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
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| CAS_supplemental =
| CAS_supplemental =
| ATC_prefix =
| ATC_prefix =
⚫
| ATC_suffix =
| UNII = TTT1F11FZB
| UNII = TTT1F11FZB
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII_Ref = {{fdacite|correct|FDA}}
| KEGG = D11299
⚫
| ATC_suffix =
| PubChem = 71249967
| PubChem = 71249967
| DrugBank_Ref =
| DrugBank_Ref =
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<!--Chemical data-->
<!--Chemical data-->
| C=25 | H=37 | N=5 | O=6
| C=25 | H=37 | N=5 | O=6
⚫
| SMILES = 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
| molecular_weight =
⚫
| smiles = 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
| StdInChI_Ref =
| StdInChI_Ref =
| StdInChI = 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
| StdInChI = 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
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}}
}}


'''Apimostinel''' (former developmental code name '''NRX-1074''') is a novel [[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]] (recently acquired by [[Allergan]] for $560 million in late 2015) for the treatment of [[major depressive disorder]].<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 | issue = | 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| url = }}</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>

==Society and culture==

===Naurex===
Naruex, the original company responsible for apimostinel, was a pharmaceutical company that developed drug candidates as [[NMDA receptor]] [[Receptor modulator|modulators]]. The company was acquired by Allergan in later 2015, who continued the clinical trials for Naurex's NMDA receptor modulator drugs. Allergan went public in 1993 as Watson Pharmaceuticals, Inc and was rebranded as Allergan in 2015 after the acquisition of several pharmaceutical companies. Allergan trades on the New York Stock Exchange under the ticker AGN.<ref>{{Cite web|url=http://www.allergan.com/investors/investors-faqs|title=Investor FAQs|website=Allergan|access-date=2016-11-20}}</ref>

In mid-2016, the acquired Naurenx, now rebranded as Aptinyx, announced a $65 million start up round with venture capital companies including New Leaf Venture Partenrs aimed towards NMDA modulation for the treatment of Parkinson's disease and PTSD.<ref>{{Cite web|url=http://www.fiercebiotech.com/naurex-vets-reprise-blockbuster-nmda-r-d-role-65m-startup-round|title=Naurex vets reprise blockbuster NMDA R&D role with $65M startup round {{!}} FierceBiotech|website=www.fiercebiotech.com|access-date=2016-11-20}}</ref>

⚫
==See also==
* [[List of investigational antidepressants]]
* [[List of investigational antidepressants]]
* [[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]



{{Antidepressants}}
{{Antidepressants}}
{{Nootropics}}
⚫
{{Glutamate receptor modulators}}


⚫
{{Ionotropic glutamate receptor modulators}}
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[[Category:Antidepressants]]

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

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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