Rapastinel

Chemical compound
  • None
Legal statusLegal status
  • US: Investigational New Drug
Identifiers
  • (S)-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]-1-[(S)-1-((2S,3R)-2-amino-3-hydroxybutanoyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carboxamide
CAS Number
  • 117928-94-6 checkY
PubChem CID
  • 14539800
ChemSpider
  • 25069944
UNII
  • 6A1X56B95E
Chemical and physical dataFormulaC18H31N5O6Molar mass413.475 g·mol−13D model (JSmol)
  • Interactive image
  • C[C@H]([C@@H](C(=O)N1CCC[C@H]1C(=O)N2CCC[C@H]2C(=O)N[C@@H]([C@@H](C)O)C(=O)N)N)O
InChI
  • InChI=1S/C18H31N5O6/c1-9(24)13(19)18(29)23-8-4-6-12(23)17(28)22-7-3-5-11(22)16(27)21-14(10(2)25)15(20)26/h9-14,24-25H,3-8,19H2,1-2H3,(H2,20,26)(H,21,27)/t9-,10-,11+,12+,13+,14+/m1/s1
  • Key:GIBQQARAXHVEGD-BSOLPCOYSA-N

Rapastinel (INNTooltip International Nonproprietary Name) (former developmental code name GLYX-13) is a novel antidepressant that was under development by Allergan (previously Naurex) as an adjunctive therapy for the treatment of treatment-resistant depression.[1][2] It is a centrally active, intravenously administered (non-orally active) amidated tetrapeptide that acts as a novel and selective modulator of the NMDA receptor.[1][2][3] The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to enhance NMDA receptor-mediated signal transduction and synaptic plasticity.[1][2][3]

Clinical development

On March 3, 2014, the U.S. FDA granted Fast Track designation to the development of rapastinel as an adjunctive therapy in treatment-resistant major depressive disorder.[4] As of 2015, the drug had completed phase II clinical development for this indication and achieved proof of concept as a rapid-acting antidepressant by demonstrating reduced depressive symptoms at days 1 through 7, as assessed by the HAM-D, without eliciting psychotomimetic or other significant side effects.[5] On January 29, 2016, Allergan (who acquired Naurex in July 2015) announced that rapastinel had received Breakthrough Therapy designation from the U.S. FDA for adjunctive treatment of major depressive disorder.[6]

On March 6, 2019, Allergan announced rapastinel failed to differentiate from placebo during phase III trials.[7] Early successful clinical studies of rapastinel in depression spurred the development of next-generation compounds with similar mechanisms of action including apimostinel (GATE-202, NRX-1074), a 2nd generation analog with improved potency, and zelquistinel (GATE-251, AGN-241751), a 3rd generation small molecule with improved potency and high oral bioavailability.[8]

Preclinical development

Rapastinel was originally invented by Joseph Moskal, the co-founder of Naurex, via structural modification of B6B21, a monoclonal antibody that similarly binds to and modulates the NMDA receptor.[2][9][10][11] Rapastinel binds to a novel and unique domain on the NMDA receptor complex that is distinct from the glycine co-agonist binding site.[3][12] Rapastinel exhibits a biphasic dose response in vitro.[3][13] At therapeutically relevant concentrations, rapastinel enhances glutamate-mediated NMDA receptor activity, independent of glycine co-agonism, and enhances the magnitude of NMDAR-mediated synaptic plasticity at excitatory synapses in the mPFC.[3][13] Positive modulation of NMDA receptors by rapastinel produces antidepressant effects that are convergent with the NMDA receptor antagonist ketamine, however, rapastinel has no ketamine-like side effects such as cognitive impairment and psychotomimetic symptoms.[14][15]

In addition to its rapid and sustained antidepressant effects, rapastinel has been shown to enhance memory and learning in both young adult and learning-impaired, aging rat models.[16] It has been shown to increase Schaffer collateral-CA1 long-term potentiation in vitro. In concert with a learning task, rapastinel has also been shown to elevate gene expression of hippocampal NR1, a subunit of the NMDA receptor, in three-month-old rats.[17] Neuroprotective effects have also been demonstrated in Mongolian Gerbils by delaying the death of CA1, CA3, and dentate gyrus pyramidal neurons under glucose and oxygen-deprived conditions.[18]

See also

References

  1. ^ a b c 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.
  2. ^ a b c d Moskal JR, Burgdorf JS, Stanton PK, Kroes RA, Disterhoft JF, Burch RM, Khan MA (2016). "The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant". Current Neuropharmacology. 15 (1): 47–56. doi:10.2174/1570159x14666160321122703. PMC 5327451. PMID 26997507.
  3. ^ a b c d e 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. ^ "FDA Grants Fast Track Designation to Naurex's Rapid-Acting Novel Antidepressant GLYX-13" (Press release) – via www.prnewswire.com.
  5. ^ Preskorn S, Macaluso M, Mehra DO, Zammit G, Moskal JR, Burch RM (March 2015). "Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent". Journal of Psychiatric Practice. 21 (2): 140–149. doi:10.1097/01.pra.0000462606.17725.93. PMID 25782764. S2CID 36800194.
  6. ^ "Allergan's Rapastinel Receives FDA Breakthrough Therapy Designation for Adjunctive Treatment of Major Depressive Disorder (MDD)". www.prnewswire.com (Press release). Retrieved 2022-05-13.
  7. ^ "Allergan Announces Phase 3 Results for Rapastinel as an Adjunctive Treatment of Major Depressive Disorder (MDD)". Archived from the original on June 22, 2023.
  8. ^ "Home - Gate Neurosciences". Archived from the original on 2023-09-05. Retrieved 2022-05-13.
  9. ^ Haring R, Stanton PK, Scheideler MA, Moskal JR (July 1991). "Glycine-like modulation of N-methyl-D-aspartate receptors by a monoclonal antibody that enhances long-term potentiation". Journal of Neurochemistry. 57 (1): 323–332. doi:10.1111/j.1471-4159.1991.tb02131.x. PMID 1828831. S2CID 37941813.
  10. ^ Moskal JR, Kuo AG, Weiss C, Wood PL, O'Connor Hanson A, Kelso S, et al. (December 2005). "GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator". Neuropharmacology. 49 (7): 1077–1087. doi:10.1016/j.neuropharm.2005.06.006. PMID 16051282. S2CID 7372648.
  11. ^ Burgdorf J, Zhang XL, Weiss C, Matthews E, Disterhoft JF, Stanton PK, Moskal JR (April 2011). "The N-methyl-D-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats". Neurobiology of Aging. 32 (4): 698–706. doi:10.1016/j.neurobiolaging.2009.04.012. PMC 3035742. PMID 19446371.
  12. ^ Pothula S, Liu RJ, Wu M, Sliby AN, Picciotto MR, Banerjee P, Duman RS (March 2021). "Positive modulation of NMDA receptors by AGN-241751 exerts rapid antidepressant-like effects via excitatory neurons". Neuropsychopharmacology. 46 (4): 799–808. doi:10.1038/s41386-020-00882-7. PMC 8027594. PMID 33059355.
  13. ^ a b Zhang XL, Sullivan JA, Moskal JR, Stanton PK (December 2008). "A NMDA receptor glycine site partial agonist, GLYX-13, simultaneously enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in hippocampus". Neuropharmacology. 55 (7): 1238–1250. doi:10.1016/j.neuropharm.2008.08.018. PMC 2661239. PMID 18796308.
  14. ^ Pothula S, Kato T, Liu RJ, Wu M, Gerhard D, Shinohara R, et al. (September 2021). "Cell-type specific modulation of NMDA receptors triggers antidepressant actions". Molecular Psychiatry. 26 (9): 5097–5111. doi:10.1038/s41380-020-0796-3. PMID 32488125. S2CID 219175373.
  15. ^ Kato T, Duman RS (January 2020). "Rapastinel, a novel glutamatergic agent with ketamine-like antidepressant actions: Convergent mechanisms". Pharmacology, Biochemistry, and Behavior. 188: 172827. doi:10.1016/j.pbb.2019.172827. PMID 31733218. S2CID 207976034.
  16. ^ Burgdorf J, Zhang XL, Weiss C, Matthews E, Disterhoft JF, Stanton PK, Moskal JR (April 2011). "The N-methyl-D-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats". Neurobiology of Aging. 32 (4): 698–706. doi:10.1016/j.neurobiolaging.2009.04.012. PMC 3035742. PMID 19446371.
  17. ^ Moskal JR, Kuo AG, Weiss C, Wood PL, O'Connor Hanson A, Kelso S, et al. (December 2005). "GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator". Neuropharmacology. 49 (7): 1077–1087. doi:10.1016/j.neuropharm.2005.06.006. PMID 16051282. S2CID 7372648.
  18. ^ Stanton PK, Potter PE, Aguilar J, Decandia M, Moskal JR (August 2009). "Neuroprotection by a novel NMDAR functional glycine site partial agonist, GLYX-13". NeuroReport. 20 (13): 1193–1197. doi:10.1097/WNR.0b013e32832f5130. PMID 19623090. S2CID 6269255.

External links

  • Rapastinel - AdisInsight
  • Rapastinel (GLYX-13) - Naurex, Inc.
  • Rapastinel Receives FDA Breakthrough Therapy Designation - Allergan plc. press release
  • v
  • t
  • e
SSRIsTooltip Selective serotonin reuptake inhibitors
SNRIsTooltip Serotonin–norepinephrine reuptake inhibitors
NRIsTooltip Norepinephrine reuptake inhibitors
NDRIsTooltip Norepinephrine–dopamine reuptake inhibitors
NaSSAsTooltip Noradrenergic and specific serotonergic antidepressants
SARIsTooltip Serotonin antagonist and reuptake inhibitors
SMSTooltip Serotonin modulator and stimulators
Others
TCAsTooltip Tricyclic antidepressants
TeCAsTooltip Tetracyclic antidepressants
Others
Non-selective
MAOATooltip Monoamine oxidase A-selective
MAOBTooltip Monoamine oxidase B-selective
Miscellaneous
  • v
  • t
  • e
AMPARTooltip α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
KARTooltip Kainate receptor
NMDARTooltip N-Methyl-D-aspartate receptor
  • See also: Receptor/signaling modulators
  • Metabotropic glutamate receptor modulators
  • Glutamate metabolism/transport modulators