Almorexant

Almorexant, 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]

Almorexant
Clinical data
Other namesACT-078573
Routes of
administration		By mouth
Drug classOrexin antagonist
ATC code
  • None
Pharmacokinetic data
MetabolismHepatic
Elimination half-life13–19 Hours[1][2]
Identifiers
  • (2R)-2-[(1S)- 6,7-Dimethoxy-1-{2-[4-(trifluoromethyl)phenyl]ethyl}-3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylacetamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC29H31F3N2O3
Molar mass512.573 g·mol−1
3D model (JSmol)
  • CNC(=O)[C@@H](C1=CC=CC=C1)N2CCC3=CC(=C(C=C3[C@@H]2CCC4=CC=C(C=C4)C(F)(F)F)OC)OC
  • InChI=1S/C29H31F3N2O3/c1-33-28(35)27(20-7-5-4-6-8-20)34-16-15-21-17-25(36-2)26(37-3)18-23(21)24(34)14-11-19-9-12-22(13-10-19)29(30,31)32/h4-10,12-13,17-18,24,27H,11,14-16H2,1-3H3,(H,33,35)/t24-,27+/m0/s1 checkY
  • Key:DKMACHNQISHMDN-RPLLCQBOSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Pharmacology

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]

History

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]

Society and culture

Names

Almorexant is the generic name of the drug and its INNTooltip International Nonproprietary Name. It is also known by its former developmental code name ACT-078573.

References
  1. 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.
  2. Hoever P, de Haas S, Winkler J, Schoemaker RC, Chiossi E, van Gerven J, Dingemanse J (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.
  3. Neubauer DN (January 2010). "Almorexant, a dual orexin receptor antagonist for the treatment of insomnia". Current Opinion in Investigational Drugs. 11 (1): 101–110. PMID 20047164.
  4. "GSK and Actelion discontinue clinical development of almorexant". GSK press release. 28 January 2011. Archived from the original on 2011-07-04.
  5. 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.
  6. Jacobson LH, Hoyer D, de Lecea L (May 2022). "Hypocretins (orexins): The ultimate translational neuropeptides". Journal of Internal Medicine. 291 (5): 533–556. doi:10.1111/joim.13406. PMID 35043499. S2CID 248119793.
  7. "Sleeping Beautifully". CBS Business Network. 24 September 2007.
  8. "Actelion Sells Glaxo Almorexant Sleep Medicine Rights". Bloomberg. 14 July 2008.
  9. "Actelion's top dollar deal leaves doubts, and little on the horizon". EP Vantage. 14 July 2008.
  10. Clinical trial number NCT00608985 for "Almorexant in Adult Subjects With Chronic Primary Insomnia (RESTORA 1)" at ClinicalTrials.gov
  11. "Actelion and GSK Discontinue Clinical Development of Almorexant". Actelion press release. 28 January 2011. Archived from the original on 2011-03-03.
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