Almorexant

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]

Almorexant

Clinical data
Other names	ACT-078573
Routes of administration	By mouth
Drug class	Orexin antagonist
ATC code	None
Pharmacokinetic data
Metabolism	Hepatic
Elimination half-life	13–19 hours[1][2]
Identifiers
IUPAC name (2R)-2-[(1S)- 6,7-Dimethoxy-1-{2-[4-(trifluoromethyl)phenyl]ethyl}-3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylacetamide
CAS Number	871224-64-5 Y 913358-93-7 (HCl)
PubChem CID	23727689
IUPHAR/BPS	2886
ChemSpider	21377865 Y
UNII	9KCW39P2EI
KEGG	D09964 N
ChEMBL	ChEMBL455136 Y
CompTox Dashboard (EPA)	DTXSID801007352
Chemical and physical data
Formula	C29H31F3N2O3
Molar mass	512.573 g·mol−1
3D model (JSmol)	Interactive image
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
InChI 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 Y Key:DKMACHNQISHMDN-RPLLCQBOSA-N Y
NY (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]

In 2014 researchers from Actelion published work indicating that almorexant had mild abuse potential but significantly less abuse potential than zolpidem.^[12]