Almorexant

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Almorexant
Almorexant.svg
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)

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]

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 INN. 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". Curr Top Med Chem. 16 (29): 3438–3469. doi:10.2174/1568026616666150929111607. PMID 26416477.
  2. ^ Hoever, P; de Haas, S; Winkler, J; Schoemaker, R C; 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 & 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. London, England. 11 (1): 101–10. PMID 20047164.
  4. ^ a b GSK and Actelion discontinue clinical development of almorexant Archived 2011-07-04 at the Wayback Machine - GSK press release, 28 Jan 2011
  5. ^ Hoch, Matthias; Gorsel, Helene van; Gerven, Joop van; Dingemanse, Jasper (2014). "Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant". The 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 (January 2022). "Hypocretins (orexins): The ultimate translational neuropeptides". J Intern Med. 291 (5): 533–556. doi:10.1111/joim.13406. PMID 35043499. S2CID 248119793.
  7. ^ Sleeping Beautifully - CBS Business Network 24 Sep 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. ^ Almorexant in Adult Subjects With Chronic Primary Insomnia (RESTORA 1). ClinicalTrials.gov (February 3, 2010). Retrieved on May 6, 2010.
  11. ^ Actelion and GSK Discontinue Clinical Development of Almorexant Archived 2011-03-03 at the Wayback Machine - Actelion press release, 28 Jan 2011

External links