Almorexant
Almorexant
Orexin antagonist compound
Almorexant (INN), also known by its development code ACT-078573, is an orexin antagonist, acting as a competitive antagonist of the OX1 and OX2 orexin receptors, which was being developed by the pharmaceutical companies Actelion and GSK for the treatment of insomnia.[3] Development of the drug was abandoned in January 2011 due to concerns over the hepatic safety of almorexant after transient increases in liver enzymes were observed in trials.[4][5]
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| Other names | ACT-078573 |
| Routes of administration | By mouth |
| Drug class | Orexin antagonist |
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| Metabolism | Hepatic |
| Elimination half-life | 13–19 hours[1][2] |
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| Formula | C29H31F3N2O3 |
| Molar mass | 512.573 g·mol−1 |
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Pharmacodynamics
Almorexant is a competitive, dual OX1 and OX2 receptor antagonist and selectively inhibits the functional consequences of OX1 and OX2 receptor activation, such as intracellular Ca2+ mobilization. It dissociates very slowly from the orexin receptors and this may prolong its duration of action.[6]
Originally developed by Actelion, from 2007 almorexant was being reported as a potential blockbuster drug, as its novel mechanism of action (orexin receptor antagonism) was thought to produce better quality sleep and fewer side effects than the traditional benzodiazepines and Z-drugs which dominated the multibillion-dollar insomnia medication market.[7]
In 2008, GlaxoSmithKline bought the development and marketing rights for almorexant from Actelion for an initial payment of $147 million.[8] The deal would have been worth an estimated $3.2 billion if the drug had successfully completed clinical development and obtained FDA approval.[9] GSK and Actelion continued to develop the drug together, and completed a Phase III clinical trial in November 2009.[10]
However, in January 2011 Actelion and GSK announced they were abandoning the development of almorexant because of its side effect profile.[4][11]
In 2014 researchers from Actelion published work indicating that almorexant had mild abuse potential but significantly less abuse potential than zolpidem.[12]
- Andrews SP, Aves SJ, Christopher JA, Nonoo R (2016). "Orexin Receptor Antagonists: Historical Perspectives and Future Opportunities". Current Topics in Medicinal Chemistry. 16 (29): 3438–3469. doi:10.2174/1568026616666150929111607. PMID 26416477.
- Hoever P, de Haas S, Winkler J, Schoemaker RC, Chiossi E, van Gerven J, et al. (May 2010). "Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant". Clinical Pharmacology and Therapeutics. 87 (5): 593–600. doi:10.1038/clpt.2010.19. PMID 20376002. S2CID 37675356.
- "GSK and Actelion discontinue clinical development of almorexant". GSK press release. 28 January 2011. Archived from the original on 2011-07-04.
- Hoch M, van Gorsel H, van Gerven J, Dingemanse J (September 2014). "Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant". Journal of Clinical Pharmacology. 54 (9): 979–986. doi:10.1002/jcph.297. PMID 24691844. S2CID 40714628.
- "Sleeping Beautifully". CBS Business Network. 24 September 2007.
- "Actelion Sells Glaxo Almorexant Sleep Medicine Rights". Bloomberg. 14 July 2008.
- "Actelion's top dollar deal leaves doubts, and little on the horizon". EP Vantage. 14 July 2008.
- Clinical trial number NCT00608985 for "Almorexant in Adult Subjects With Chronic Primary Insomnia (RESTORA 1)" at ClinicalTrials.gov
- "Actelion and GSK Discontinue Clinical Development of Almorexant". Actelion press release. 28 January 2011. Archived from the original on 2011-03-03.
- Cruz HG, Hoever P, Chakraborty B, Schoedel K, Sellers EM, Dingemanse J (April 2014). "Assessment of the abuse liability of a dual orexin receptor antagonist: a crossover study of almorexant and zolpidem in recreational drug users". CNS Drugs. 28 (4): 361–372. doi:10.1007/s40263-014-0150-x. PMID 24627301.