Chemistry:Blixeprodil

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Blixeprodil,[1] 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.[2][3][4][5][6][7] It is taken by mouth.[2][4][5]

The drug is orally active, in contrast to the poor oral bioavailability of ketamine.[5] Its oral bioavailability is >60%.[8][9] The time to peak levels of blixeprodil is 1.5 hours and its elimination half-life is 4.3 hours.[8]

Blixeprodil shows antidepressant-like effects in rodents.[5][10][8][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.[5][6][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.[4][8] However, dissociative and other related effects have been observed at low incidences and at higher doses.[8]

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.[2][3][4] 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.[2][3][4]

See also

References

  1. ↑ 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"
  2. ↑ 2.0 2.1 2.2 2.3 "GM 1020". 12 July 2024. https://adisinsight.springer.com/drugs/800067964. 
  3. ↑ 3.0 3.1 3.2 "Delving into the Latest Updates on GM-1020 with Synapse". 15 February 2025. https://synapse.patsnap.com/drug/f50bdb78636a4be2a647ced81699eca9. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Next-generation psychedelics: should new agents skip the trip?". Nature Biotechnology 42 (6): 827–830. June 2024. 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.". 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "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. May 2024. doi:10.1038/s41386-023-01783-1. PMID 38177696. 
  6. ↑ 6.0 6.1 "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. 2023. doi:10.1016/j.biopsych.2023.02.771. 
  7. ↑ "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). December 2024. doi:10.1038/s41386-024-02010-1. PMID 39643632. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 "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). December 2023. doi:10.1038/s41386-023-01756-4. PMID 38040810. 
  9. ↑ 9.0 9.1 9.2 9.3 "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). December 2022. doi:10.1038/s41386-022-01484-1. PMID 36456693. 
  10. ↑ "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. August 2024. doi:10.1016/j.yrtph.2024.105666. PMID 38942190. 
  11. ↑ "Avaliação farmacológica de um análogo a um antagonista do receptor N-Metil-D-Aspartato". I Congresso de Ciências Farmacêuticas do Interior Baiano. 2015. https://www.crf-ba.org.br/wp-content/uploads/2024/05/Avaliacao-farmacologica-de-um-analogo-a-um-antagonista-do-receptor-N-Metil-D-Aspartato.pdf. "[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. ↑ "Gilgamesh Tweaks Known Psychedelics To Improve Therapies". 31 January 2023. https://www.lucid.news/gilgamesh-tweaks-psychedelics/. 



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