Chemistry:Deramciclane

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Deramciclane (developmental code names EGIS-3886, EXV-801) is an experimental drug which was studied for the treatment of anxiety disorders but was never marketed.[1][2] It has since been repurposed for the treatment of agitation, both alone (as EXV-801) and in combination with dextromethorphan (DXM) (as EXV-802).[3][4] The drug acts as a serotonin 5-HT2A receptor antagonist, serotonin 5-HT2C receptor inverse agonist, GABA reuptake inhibitor, and weak CYP2D6 inhibitor.[1][3][4]

Side effects

Clinical studies have found that deramciclane is well-tolerated in humans at dosages ranging between 0.2–150 mg.[5] All reported side effects were mild-moderate with the most common side effect being headache and dizziness. No severe side effects were reported in any clinical trial, and no side effects were found to be dose-dependent.[5] Trial participants showed no significant increases in liver enzyme activity[6] and no changes in ECGs,[6] systolic blood pressure, diastolic blood pressure, HDL cholesterol, or LDL cholesterol levels.[7] Another advantage to deramciclane is that it did not produce any withdrawal effects after long-term studies, like other anxiolytics do.

Pharmacology

Pharmacodynamics

Deramciclane acts as an antagonist at the serotonin 5-HT2A receptor,[8] as an inverse agonist at the serotonin 5-HT2C receptor,[9] and as a GABA reuptake inhibitor,[10] Some studies also show the drug to have moderate affinity to dopamine D2 receptors and low affinity to dopamine receptor D1.[6] Activation of the serotonin 5-HT2A and 5-HT2C receptors has been implicated in anxiety and mood.[11]

Deramciclane does not affect CYP3A4 activity in metabolizing other drugs,[12] but it is a weak inhibitor of CYP2D6.[13]

Pharmacokinetics

There have been several clinical studies to examine the pharmacokinetics of deramciclane, which can readily cross the blood–brain barrier.[8][14] Overall, studies show that deramciclane follows linear pharmacokinetics in humans with oral daily doses ranging from 3–150 mg and twice daily doses ranging from 10–60 mg.[6] Additionally, no differences have been found in adsorption, distribution, metabolism, or elimination when an oral dose is administered in tablet or capsule form.[5]

Deramciclane is rapidly absorbed from the gastrointestinal tract. Studies show that the drug can be detected in plasma as quickly as 20 minutes after dosing.[5] Deramciclane demonstrates a Tmax of 2–4 hours and is unaffected by dosage.[6][7] The Cmax at this time is approximately 140 ng/mL.[6] A typical PTF (peak trough fluctuation) is 70-80% over four weeks of administration, and is unaffected by dose.[6][7] The oral tablet of deramciclane yields a bioavailability of 36% on average,[6] which is considered decent enough for oral administration and avoid the necessity of a more invasive route.[15]

The pharmacokinetics of deramciclane are also studied in rats, mice, rabbits, and dogs. Rat and rabbits show the fastest metabolism rates of the drug, and dogs are the only animals to show non-linear pharmacokinetics of deramciclane.[16] Phase I metabolism in rat hepatocytes is similar enough to that in humans that the rat can be used as a predictive model for human metabolism of deramciclane.[16] In rats, the Tmax is found to be 0.5 hours after a single 10 mg/kg dose and the half-life of deramciclane is about 3.5-5.5 hours.[17] As expected, deramciclane reaches greatest peak plasma concentrations with intravenous administration, followed by intraperitoneal, then oral administration with the lowest peak plasma concentration.[17]

Studies assessing the elimination half-life of deramciclane point to a range of 20–32 hours for T1/2.[5][18] The elimination half-life appears to increase with dosage.[7] There is some evidence for accumulation of deramciclane, though it is a topic of debate.[6][7]

Deramciclane undergoes side chain modification and oxidation at multiple positions on the molecule.[16] The side chain reaction forms phenylborneol and N-desmethylderamciclane which is the active metabolite of deramciclane.[16] Oxidation of the molecule results in many hydroxy-, carboxy-, and N-oxide derivatives.[16]

Clinical studies investigating the effects of food or lack thereof on deramciclane adsorption show that there is a statistically significant, but not clinically relevant, increase in bioavailability of deramciclane when administered with food because the point of critical instability of deramciclane is relatively low at a pH of 2. The presence of food does not affect deramciclane's elimination half-life (T1/2) or mean residence time (MRT).[19]

History

Deramciclane was discovered by EGIS Pharmaceuticals Ltd in Budapest, Hungary. In 2000, EGIS signed over exclusive rights to Orion Pharma to further develop, register, and market deramciclane. Successful pre-clinical, Phase I, and Phase II trials looked promising to the company and its investors even up until the third quarter of 2002.[20] Phase I studies show little to no side effects of deramciclane.[6][19][5][7] Phase II studies show little to no side effects and statistically significant improvement on the Hamilton Anxiety Rating Scale in response to daily 60 mg doses, but not in response to daily 10 or 30 mg doses.[21] Finally, in February, 2003, deramciclane development for use against general anxiety disorder (GAD) was discontinued during Phase III trials due to clinically insignificant results compared to placebo groups.[20]

Research

Anxiety

Deramciclane was studied for the treatment of generalized anxiety disorder (GAD) and reached phase 3 clinical trials for this indication, but development was discontinued in 2003.[1]

Agitation

Deramciclane, under the developmental code name EXV-801, is under development for the treatment of agitation.[3] It is being developed by Exciva.[3] The drug is also being developed for this indication in combination with dextromethorphan (DXM) under the code name EXV-802 (also known as Deraphan).[4][22][23] As of March 2026, deramciclane is in phase 2/3 clinical trials for treatment of agitation.[3][22][4]

See also

  • Tiagabine, another GABA reuptake inhibitor
  • List of investigational agitation drugs

References

  1. ↑ 1.0 1.1 1.2 "Deramciclane". 26 February 2003. https://adisinsight.springer.com/drugs/800001479. 
  2. ↑ Orion Pharma Inlicenses Deramciclane from Egis Pharmaceuticals. Phase 3 Program in Anxiety has Started, 2000 http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=29979
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "EXV 801". 17 March 2026. https://adisinsight.springer.com/drugs/800085769. 
  4. ↑ 4.0 4.1 4.2 4.3 "Deraphan". 12 March 2026. https://www.alzforum.org/therapeutics/deraphan. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "The single dose pharmacokinetics and safety of deramciclane in healthy male volunteers". Biopharmaceutics & Drug Disposition 20 (7): 327–34. October 1999. doi:10.1002/(SICI)1099-081X(199910)20:7<327::AID-BDD192>3.0.CO;2-8. PMID 10760840. 
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 "Pharmacokinetics of deramciclane and N-desmethylderamciclane after single and repeated oral doses in healthy volunteers". International Journal of Clinical Pharmacology and Therapeutics 42 (8): 449–55. August 2004. doi:10.5414/cpp42449. PMID 15366325. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "Pharmacokinetics and safety of deramciclane during multiple oral dosing". International Journal of Clinical Pharmacology and Therapeutics 37 (12): 589–97. December 1999. PMID 10599951. 
  8. ↑ 8.0 8.1 "Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration--a positron emission tomography study". Psychopharmacology 145 (1): 76–81. July 1999. doi:10.1007/s002130051034. PMID 10445375. 
  9. ↑ "Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation". Psychopharmacology 136 (2): 99–104. March 1998. doi:10.1007/s002130050544. PMID 9551765. 
  10. ↑ "Inhibition of high-affinity synaptosomal uptake of gamma-aminobutyric acid by a bicyclo-heptane derivative". Arzneimittel-Forschung 39 (3): 295–7. March 1989. PMID 2502985. 
  11. ↑ "The therapeutic role of 5-HT1A and 5-HT2A receptors in depression". Journal of Psychiatry & Neuroscience 29 (4): 252–65. July 2004. PMID 15309042. 
  12. ↑ "Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone". European Journal of Clinical Pharmacology 59 (10): 761–6. December 2003. doi:10.1007/s00228-003-0674-3. PMID 14566442. 
  13. ↑ "Effect of the novel anxiolytic drug deramciclane on cytochrome P(450) 2D6 activity as measured by desipramine pharmacokinetics". European Journal of Clinical Pharmacology 59 (12): 893–8. February 2004. doi:10.1007/s00228-003-0714-z. PMID 14730412. 
  14. ↑ "Deramciclane improves object recognition in rats: potential role of NMDA receptors". Pharmacology, Biochemistry, and Behavior 94 (4): 570–4. February 2010. doi:10.1016/j.pbb.2009.11.012. PMID 19963003. 
  15. ↑ "Pharmacokinetics of deramciclane, a novel anxiolytic agent, after intravenous and oral administration". Drugs in R&D 4 (6): 339–45. 2003. doi:10.2165/00126839-200304060-00002. PMID 14584962. 
  16. ↑ 16.0 16.1 16.2 16.3 16.4 "Biotransformation of deramciclane in primary hepatocytes of rat, mouse, rabbit, dog, and human". Drug Metabolism and Disposition 33 (11): 1708–16. November 2005. doi:10.1124/dmd.105.003764. PMID 16118331. 
  17. ↑ 17.0 17.1 "Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane and its N-desmethyl metabolite in the rat". The Journal of Pharmacy and Pharmacology 52 (1): 47–51. January 2000. doi:10.1211/0022357001773670. PMID 10716602. 
  18. ↑ "A prospective study of depression and immune dysregulation in multiple sclerosis". Archives of Neurology 49 (3): 238–44. March 1992. doi:10.1001/archneur.1992.00530270052018. PMID 1536625. 
  19. ↑ 19.0 19.1 "Influence of food on the oral bioavailability of deramciclane from film-coated tablet in healthy male volunteers". European Journal of Pharmaceutics and Biopharmaceutics 58 (3): 689–95. November 2004. doi:10.1016/j.ejpb.2004.03.036. PMID 15451546. 
  20. ↑ 20.0 20.1 Blow to Orion as deramciclane fails in Phase III anxiety studies, 2003 http://www.thepharmaletter.com/article/blow-to-orion-as-deramciclane-fails-in-phase-iii-anxiety-studies
  21. ↑ "Deramciclane in the treatment of generalized anxiety disorder: a placebo-controlled, double-blind, dose-finding study". European Neuropsychopharmacology 15 (6): 617–23. December 2005. doi:10.1016/j.euroneuro.2005.03.002. PMID 15949921. 
  22. ↑ 22.0 22.1 "Phase 2/3, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of EXV-802 and EXV-801 in the Treatment of Agitation in Participants With Alzheimer's Disease Dementia". 10 March 2026. https://adisinsight.springer.com/trials/700388876. 
  23. ↑ "ClinicalTrials.gov". https://clinicaltrials.gov/study/NCT07284472. 



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