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'''Apimostinel''' 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''' 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.


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, unlike rapastinel (which 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. 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" />
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, unlike rapastinel (which 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]], but has been [[molecular modification|structurally modified]] and [[benzyl]]ated. 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" />


Commercial competitors of the drug include Cerecor's [[CERC-301]], [[4-Chlorokynurenine|AV-101]] from VistaGen Therapeutics,<sup>[[CERC-301#cite note-8|[8]]]</sup> and [[PT00114]] from [[Protagenic]].{{Citation needed|date=November 2016}}
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 ==
==Society and culture==


=== Naurex ===
===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>
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>
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 ==
==See also==
⚫
* [[Buprenorphine/samidorphan]]
* [[4-Chlorokynurenine]] (AV-101)
⚫
* [[Buprenorphine/samidorphan]] (ALKS-5461)
* [[CERC-301]]
* [[Esketamine]]
* [[Esketamine]]
* [[Ketamine]]
* [[Ketamine]]
* [[Neboglamine]] (nebostinel)
* [[Neboglamine]]
* [[NSI-189]]
* [[NSI-189]]


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==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}}
Line 84: Line 83:
{{Glutamatergics}}
{{Glutamatergics}}


⚫
[[Category:Carboxamides]]
[[Category:Antidepressants]]
[[Category:Antidepressants]]
⚫
[[Category:Carboxamides]]
[[Category:NMDA receptor agonists]]
[[Category:NMDA receptor agonists]]
[[Category:Peptides]]
[[Category:Pyrrolidines]]
[[Category:Pyrrolidines]]

Revision as of 00:15, 21 December 2016

Apimostinel
Clinical data
Other namesNRX-1074, AGN-241660, Threonyl-prolyl-2R-(2-benzyl)-prolyl-threonine amide
Legal status
Legal status
  • Investigational New Drug
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
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 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.[1][2][3][4][5] As of 2015, an intravenous formulation of apimostinel is in a phase II clinical trial for MDD,[3][6] and an oral formulation is concurrently in phase I trials for MDD.

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, unlike rapastinel (which must be administered via intravenous injection), is orally-active.[3] Apimostinel is intended by Naurex as an improved, follow-up drug to rapastinel. Similarly to rapastinel, apimostinel is an amidated tetrapeptide, but has been structurally modified and benzylated. The drug has shown rapid antidepressant effects in pre-clinical models of depression.[3] In addition, similarly to rapastinel, it is well-tolerated and lacks the schizophrenia-like psychotomimetic effects of other NMDA receptor antagonists such as ketamine.[3]

Commercial competitors of apimostinel include AV-101 from VistaGen Therapeutics and Cerecor's CERC-301.[8]

Society and culture

Naurex

Naruex, the original company responsible for apimostinel, was a pharmaceutical company that developed drug candidates as NMDA receptor 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.[7]

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.[8]

See also

References

  1. ^ Hayley S, Litteljohn D (2013). "Neuroplasticity and the next wave of antidepressant strategies". Front Cell Neurosci. 7: 218. doi:10.3389/fncel.2013.00218. PMC 3834236. PMID 24312008. 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).{{cite journal}}: CS1 maint: unflagged free DOI (link)
  2. ^ PR Newswire (2010). "Naurex's Novel Antidepressant GLYX-13 Recognized as One of Windhover's Top 10 Neuroscience Projects to Watch".
  3. ^ a b c d e PR Newswire (2014). "Naurex Reports Positive Top-Line Phase 2b Results for Novel Antidepressant GLYX-13 and Advances NRX-1074 into Phase 2 Depression Study".
  4. ^ Dang YH, Ma XC, Zhang JC, et al. (January 2014). "Targeting of NMDA Receptors in the Treatment of Major Depression". Curr. Pharm. Des. 20 (32): 5151–9. doi:10.2174/1381612819666140110120435. PMID 24410564.
  5. ^ plc, Allergan. "Allergan Successfully Completes Naurex Acquisition". www.prnewswire.com. Retrieved 2016-11-20.
  6. ^ "Study of Intravenous NRX-1074 in Patients With Major Depressive Disorder". Clinicaltrials.gov. US National Institutes of Health. Retrieved 10 December 2014.
  7. ^ "Investor FAQs". Allergan. Retrieved 2016-11-20.
  8. ^ "Naurex vets reprise blockbuster NMDA R&D role with $65M startup round | FierceBiotech". www.fiercebiotech.com. Retrieved 2016-11-20.


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