Almorexant (
INN), also known by its development code ACT-078573, is an
orexin antagonist, acting as a competitive
antagonist of the OX1 and OX2orexin 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 IIIclinical 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]
References
^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.
PMID26416477.
^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.
PMID20376002.
S2CID37675356.
^Neubauer DN (January 2010). "Almorexant, a dual orexin receptor antagonist for the treatment of insomnia". Current Opinion in Investigational Drugs. 11 (1): 101–110.
PMID20047164.
^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.
PMID24691844.
S2CID40714628.
^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.
PMID35043499.
S2CID248119793.
^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.
PMID24627301.