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Rapastinel
Clinical data
Other names	GLYX-13; BV-102
Routes of; administration	Intravenous
Drug class	Selective NMDA receptor modulator
ATC code	None;
Legal status
Legal status	US: Investigational New Drug;
Identifiers
	IUPAC name (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 ;
PubChem CID	14539800;
ChemSpider	25069944;
UNII	6A1X56B95E;
CompTox Dashboard (EPA)	DTXSID501030481 ;
Chemical and physical data
Formula	C18H31N5O6
Molar mass	413.475 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES 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]