almorexant
{{Short description|Orexin antagonist compound}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477318417
| IUPAC_name = (2R)-2-[(1S)- 6,7-Dimethoxy-1-{2-[4-(trifluoromethyl)phenyl]ethyl}-3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylacetamide
| image = Almorexant.svg
| width = 200px
| tradename =
| routes_of_administration = By mouth
| class = Orexin antagonist
| bioavailability =
| metabolism = Hepatic
| elimination_half-life = 13–19 hours{{cite journal | vauthors = Andrews SP, Aves SJ, Christopher JA, Nonoo R | title = Orexin Receptor Antagonists: Historical Perspectives and Future Opportunities | journal = Current Topics in Medicinal Chemistry | volume = 16 | issue = 29 | pages = 3438–3469 | date = 2016 | pmid = 26416477 | doi = 10.2174/1568026616666150929111607 }}{{cite journal | vauthors = Hoever P, de Haas S, Winkler J, Schoemaker RC, Chiossi E, van Gerven J, Dingemanse J | title = Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant | journal = Clinical Pharmacology and Therapeutics | volume = 87 | issue = 5 | pages = 593–600 | date = May 2010 | pmid = 20376002 | doi = 10.1038/clpt.2010.19 | s2cid = 37675356 }}
| IUPHAR_ligand = 2886
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 871224-64-5
| CAS_supplemental =
913358-93-7 (HCl)
| ATC_prefix = None
| ATC_suffix =
| ATC_supplemental =
| PubChem = 23727689
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 21377865
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 9KCW39P2EI
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 455136
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D09964
| synonyms = ACT-078573
| C=29 | H=31 | F=3 | N=2 | O=3
| SMILES = 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
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DKMACHNQISHMDN-RPLLCQBOSA-N
}}
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.{{cite journal | vauthors = Neubauer DN | title = Almorexant, a dual orexin receptor antagonist for the treatment of insomnia | journal = Current Opinion in Investigational Drugs | volume = 11 | issue = 1 | pages = 101–110 | date = January 2010 | pmid = 20047164 | doi = }} 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.{{cite web | url = http://www.gsk.com/media/pressreleases/2011/2011_pressrelease_10019.htm | title = GSK and Actelion discontinue clinical development of almorexant | archive-url = https://web.archive.org/web/20110704194943/http://www.gsk.com/media/pressreleases/2011/2011_pressrelease_10019.htm | archive-date=2011-07-04 | work = GSK press release | date = 28 January 2011 }}{{cite journal | vauthors = Hoch M, van Gorsel H, van Gerven J, Dingemanse J | title = Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant | journal = Journal of Clinical Pharmacology | volume = 54 | issue = 9 | pages = 979–986 | date = September 2014 | pmid = 24691844 | doi = 10.1002/jcph.297 | s2cid = 40714628 }}
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.{{cite journal | vauthors = Jacobson LH, Hoyer D, de Lecea L | title = Hypocretins (orexins): The ultimate translational neuropeptides | journal = Journal of Internal Medicine | volume = 291 | issue = 5 | pages = 533–556 | date = May 2022 | pmid = 35043499 | doi = 10.1111/joim.13406 | s2cid = 248119793 }}
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.{{cite web | url = http://findarticles.com/p/articles/mi_hb5255/is_18/ai_n29394606/ | title = Sleeping Beautifully | work = CBS Business Network | date = 24 September 2007 }}
In 2008, GlaxoSmithKline bought the development and marketing rights for almorexant from Actelion for an initial payment of $147 million.{{cite web | url = https://www.bloomberg.com/apps/news?pid=newsarchive&sid=aAS6UsbXi2M8 | title = Actelion Sells Glaxo Almorexant Sleep Medicine Rights | work = Bloomberg | date = 14 July 2008 }} The deal would have been worth an estimated $3.2 billion if the drug had successfully completed clinical development and obtained FDA approval.{{cite web | url = http://www.epvantage.com/Universal/View.aspx?type=Story&id=159945&isEPVantage=yes | title = Actelion's top dollar deal leaves doubts, and little on the horizon | work = EP Vantage | date = 14 July 2008 }} GSK and Actelion continued to develop the drug together, and completed a Phase III clinical trial in November 2009.{{ClinicalTrialsGov|NCT00608985|Almorexant in Adult Subjects With Chronic Primary Insomnia (RESTORA 1)}}
However, in January 2011 Actelion and GSK announced they were abandoning the development of almorexant because of its side effect profile.{{cite web | url = http://www.actelion.com/en/our-company/news-and-events/index.page?newsId=1483135 | title = Actelion and GSK Discontinue Clinical Development of Almorexant | archive-url = https://web.archive.org/web/20110303032221/http://www1.actelion.com/en/our-company/news-and-events/index.page?newsId=1483135 | archive-date=2011-03-03 | work = Actelion press release | date = 28 January 2011 }}
In 2014 researchers from Actelion published work indicating that almorexant had mild abuse potential but significantly less abuse potential than zolpidem.{{cite journal | vauthors = Cruz HG, Hoever P, Chakraborty B, Schoedel K, Sellers EM, Dingemanse J | title = Assessment of the abuse liability of a dual orexin receptor antagonist: a crossover study of almorexant and zolpidem in recreational drug users | journal = CNS Drugs | volume = 28 | issue = 4 | pages = 361–372 | date = April 2014 | pmid = 24627301 | doi = 10.1007/s40263-014-0150-x }}
References
{{Reflist}}
External links
- [https://web.archive.org/web/20080514235534/http://www.actelion.com/ Actelion's official website]
{{Orexin receptor modulators}}