Zelquistinel

Zelquistinel
Clinical data
Routes of
administration		By mouth
Drug classNMDA receptor modulator
Pharmacokinetic data
Bioavailability~100%
Elimination half-life1.2–2 hours
Identifiers
  • tert-butyl (4S)-2-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]-3-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC15H25N3O5
Molar mass327.381 g·mol−1
3D model (JSmol)
  • C[C@H]([C@@H](C(=O)N)N1C[C@]2(C1=O)CCCN2C(=O)OC(C)(C)C)O
  • InChI=1S/C15H25N3O5/c1-9(19)10(11(16)20)17-8-15(12(17)21)6-5-7-18(15)13(22)23-14(2,3)4/h9-10,19H,5-8H2,1-4H3,(H2,16,20)/t9-,10+,15+/m1/s1
  • Key:ABAPCYNTEPGBNJ-FTGAXOIBSA-N

Zelquistinel (GATE-251, formerly AGN-241751) is an orally active small-molecule NMDA receptor modulator which is under development for the treatment of major depressive disorder (MDD) by Gate Neurosciences, and previously by Allergan.[1][2][3]

Zelquistinel 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.[4][5] Its mechanism of action is similar to that of rapastinel. However, unlike rapastinel, zelquistinel is orally bioavailable, exhibits increased potency, and has improved drug properties.[2][3][5] The mean half-life of Zelquistinel is reported to be from 1.21 to 2.06 hours, reaching peak plasma concentrations 30 minutes after administration.[6] In preclinical studies, single doses of zelquistinel demonstrated both rapid-acting (24-hours) and sustained (1-week) antidepressant-like effects and enhancement of long-term synaptic plasticity.[6]

On July 23, 2018, the U.S. FDA granted Fast Track designation to the development of zelquistinel as an investigational new treatment for major depressive disorder.[7]

In 2019, Allergan completed an exploratory phase IIa clinical trial of once-weekly oral zelquistinel in major depressive disorder.[1][3][8] As of 2024, zelquistinel is undergoing a phase IIb clinical trial for depression sponsored by Gate Neurosciences.[2]

  1. ^ a b "NMDA receptor modulators - AdisInsight". adisinsight.springer.com.
  2. ^ a b c "Home - Gate Neurosciences". Retrieved 2022-05-12.
  3. ^ a b c Aptinyx Inc. "Allergan Exercises Option to Acquire Compound from Aptinyx Discovery Platform Under Ongoing Research Collaboration". www.prnewswire.com (Press release).
  4. ^ 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.
  5. ^ a b 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.
  6. ^ a b Burgdorf JS (26 July 2022). "Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects". International Journal of Neuropsychopharmacology.
  7. ^ plc A. "Allergan Receives FDA Fast Track Designation for AGN-241751 for the Treatment of Major Depressive Disorder (MDD)". www.prnewswire.com (Press release). Retrieved 2022-05-16.
  8. ^ Clinical trial number NCT03586427 for "A Double-Blind, Placebo-Controlled, Fixed-Dose Study of AGN-241751 in Adult Participants With Major Depressive Disorder" at ClinicalTrials.gov