Blixeprodil

Last updated

Blixeprodil
Blixeprodil.svg
Clinical data
Other namesGM-1020; GM1020; (R)-4-Fluorodeschloroketamine; (R)-4-FDCK; (R)-4FDCK
Routes of
administration 		Oral [1] [2] [3]
Drug class NMDA receptor antagonist [1] [2] [3]
Pharmacokinetic data
Bioavailability >60% [4]
Elimination half-life 4.3 hours [4]
Identifiers
  • (2R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one
CAS Number
PubChem CID
Chemical and physical data
Formula C13H16FNO
Molar mass 221.275 g·mol−1
3D model (JSmol)
  • CN[C@]1(CCCCC1=O)C2=CC=C(C=C2)F
  • InChI=1S/C13H16FNO/c1-15-13(9-3-2-4-12(13)16)10-5-7-11(14)8-6-10/h5-8,15H,2-4,9H2,1H3/t13-/m1/s1
  • Key:GLHWPYBETIKGHM-CYBMUJFWSA-N

Blixeprodil, [5] also known by its developmental code name GM-1020 or as (R)-4-fluorodeschloroketamine ((R)-4-FDCK), is an NMDA receptor antagonist related to ketamine which is under development for the treatment of major depressive disorder, bipolar depression, and other depressive disorders. [1] [6] [2] [3] [7] [8] It is taken by mouth. [1] [2] [3]

The drug is orally active, in contrast to the poor oral bioavailability of ketamine. [3] Its oral bioavailability is >60%. [4] [9] The time to peak levels of blixeprodil is 1.5 hours and its elimination half-life is 4.3 hours. [4]

Blixeprodil shows antidepressant-like effects in rodents. [3] [10] [4] [9] It appears to have a greater separation between antidepressant-like and ataxia-inducing doses than ketamine in rodents and hence might have better tolerability. [3] [7] [9] Whereas ketamine shows only 3-fold separation between antidepressant-like and ataxic doses, there was 13-fold separation for blixeprodil, and it did not produce hyperlocomotion at doses >20-fold higher than the minimum antidepressant-like dose. [9] In relation to the preceding, blixeprodil is claimed to be non-dissociative at therapeutic doses. [2] [4] However, dissociative and other related effects have been observed at low incidences and at higher doses. [4]

The drug is a close analogue of ketamine, with a 4-fluoro group instead of a 2-chloro group on the phenyl ring and in (2R)-enantiopure form. [11] Hence, blixeprodil is related to arketamine ((R)-ketamine); it is said to bet on the notion that arketamine is importantly involved in the antidepressant effects of ketamine, in spite of arketamine having less propensity for inducing dissociation. [12]

Blixeprodil is being developed by Gilgamesh Pharmaceuticals. [1] [6] [2] As of July 2024, it is in phase 2 clinical trials for major depressive disorder and bipolar depression and is in phase 1 trials for other depressive disorders. [1] [6] [2]

See also

References

  1. 1 2 3 4 5 6 "GM 1020". AdisInsight. 12 July 2024. Retrieved 20 February 2025.
  2. 1 2 3 4 5 6 7 Peplow M (June 2024). "Next-generation psychedelics: should new agents skip the trip?". Nature Biotechnology. 42 (6): 827–830. doi:10.1038/s41587-024-02285-1. PMID   38831049. Other companies are confident that they can further reduce or even erase those effects without losing therapeutic efficacy. Gilgamesh, for example, is taking that approach with ketamine, DMT and psilocybin. In the case of ketamine, says Kruegel, the dissociative side effects require that the subjects remain under supervision. So Gilgamesh designed a ketamine analog called GM-1020 that has no dissociative effects (distortions in sight, sound and feelings of detachment) and that also has better oral bioavailability than ketamine itself. After completing a phase 1 trial last year, the company began dosing patients with GM-1020 in a phase 2 trial for major depressive disorder in March. "The hope is that the psychoactive effects will be limited enough that this can eventually be taken at home," says Kruegel.
  3. 1 2 3 4 5 6 7 Klein AK, Austin EW, Cunningham MJ, Dvorak D, Gatti S, Hulls SK, et al. (May 2024). "GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents". Neuropsychopharmacology. 49 (6): 905–914. doi:10.1038/s41386-023-01783-1. PMC   11039472 . PMID   38177696.
  4. 1 2 3 4 5 6 7 Marek G, Umbricht D, Christian E, Winters J, Raines S, Kiss L, et al. (December 2023). "ACNP 62nd Annual Meeting: Poster Abstracts P251 – P500: P352. GM-1020: An Oral NMDA Receptor Antagonist for Depression Demonstrates Target Engagement at Doses That Do Not Cause Dissociation, Ataxia or Sedation in a Phase 1 Single Ascending Dose Study". Neuropsychopharmacology. 48 (Suppl 1): 211–354 (269–269). doi:10.1038/s41386-023-01756-4. PMC   10729596 . PMID   38040810.
  5. ↑ https://iris.who.int/bitstream/handle/10665/380497/9789240107038-eng.pdf "blixeprodilum blixeprodil (2R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one N-methyl-D-aspartate (NMDA) receptor antagonist"
  6. 1 2 3 "Delving into the Latest Updates on GM-1020 with Synapse". Synapse. 15 February 2025. Retrieved 20 February 2025.
  7. 1 2 Klein A, Dvorak D, Austin E, Marek G, Sporn J, Hughes Z, et al. (2023). "531. GM-1020 is a Novel, Orally Bioavailable NMDA Antagonist With Improved Separation Between Antidepressant and Ataxic Doses Compared to Ketamine". Biological Psychiatry. 93 (9): S308 –S309. doi:10.1016/j.biopsych.2023.02.771.
  8. ↑ Hughes Z (December 2024). "ACNP 63rd Annual Meeting: Panels, Mini-Panels and Study Groups: 19.4 Translational Profile of GM-1020, a Novel Orally Bioavailable NMDA Receptor Antagonist That Achieves Robust Target Engagement Without Dissociation or Sedation". Neuropsychopharmacology. 49 (Suppl 1): 1–64 (25–25). doi:10.1038/s41386-024-02010-1. PMC  11627185. PMID   39643632.
  9. 1 2 3 4 Kiss L, Klein A, Austin E, Dvorak D, Gatti S, Papp M, et al. (December 2022). "ACNP 61st Annual Meeting: Poster Abstracts P1 - P270: P215. GM-1020: A Novel, Orally Bioavailable NMDA Receptor Antagonist With Rapid and Robust Antidepressant Effects and Reduced Ataxia in Rodents". Neuropsychopharmacology. 47 (Suppl 1): 63–219 (185–186). doi:10.1038/s41386-022-01484-1. PMC   9714397 . PMID   36456693.
  10. ↑ Trunnell ER, Baines J, Farghali S, Jackson T, Jayne K, Smith R, et al. (August 2024). "The need for guidance in antidepressant drug development: Revisiting the role of the forced swim test and tail suspension test". Regulatory Toxicology and Pharmacology. 151: 105666. doi:10.1016/j.yrtph.2024.105666. PMID   38942190.
  11. ↑ Sá VL, de Jesus Santos G, da Fonseca Fraga I, da Silva JM, Santos, MG, et al. (2015). Avaliação farmacológica de um análogo a um antagonista do receptor N-Metil-D-Aspartato [Pharmacological evaluation of an analogue of an N-Methyl-D-Aspartate receptor antagonist](PDF). I Congresso de Ciências Farmacêuticas do Interior Baiano. [Translated:] [...] ketamine has low oral availability and a narrow therapeutic index, generating adverse effects such as dissociation, cognitive impairment, sedation, and ataxia, which limits the acceptance of the drug in the treatment of depression. The preclinical characterization through in vitro and in vivo studies of GM-1020 ((R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one) may indicate a new therapy that presents bioavailability when administered orally and absence of undesirable motor effects.
  12. ↑ Gunther M (31 January 2023). "Gilgamesh Tweaks Known Psychedelics To Improve Therapies". Lucid News - Psychedelics, Consciousness Technology, and the Future of Wellness. Retrieved 20 February 2025.
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