Filorexant

Filorexant (INN, USAN; developmental code name MK-6096) is an orexin antagonist which was under development by Merck for the treatment of insomnia, depression, diabetic neuropathy, and migraine.[2][3] It is a dual antagonist of the orexin OX1 and OX2 receptors.[4][5] It has a relatively short elimination half-life of 3 to 6 hours.[1] However, it dissociates slowly from the orexin receptors and may thereby have a longer duration.[6] Possibly in relation to this, filorexant shows next-day somnolence similarly to suvorexant.[6] In phase 2 clinical trials, filorexant was found to be effective in the treatment of insomnia,[7] but was not effective in the treatment of major depressive disorder,[8][9][10] painful diabetic neuropathy,[11][12] or migraine.[13] As of May 2015, filorexant was no longer listed on Merck's online development pipeline and hence development of the drug appears to have been discontinued.[14][1][2] Development of filorexant may have been discontinued due to lack of differentiation from suvorexant (which was also developed by Merck).[6]

Filorexant
Clinical data
Other namesMK-6096; MK6096
Routes of
administration		By mouth
Drug classOrexin antagonist
ATC code
  • None
Pharmacokinetic data
Elimination half-life3–6 hours[1]
Identifiers
IUPAC name
  • [(2R,5R)-5-{[(5-Fluoro-2-pyridinyl)oxy]methyl}-2-methyl-1-piperidinyl][5-methyl-2-(2-pyrimidinyl)phenyl]methanone
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.203.042
Chemical and physical data
FormulaC24H25FN4O2
Molar mass420.488 g·mol−1
3D model (JSmol)
SMILES
  • C[C@@H]1CC[C@H](CN1C(=O)C2=C(C=CC(=C2)C)C3=NC=CC=N3)COC4=NC=C(C=C4)F
InChI
  • InChI=1S/C24H25FN4O2/c1-16-4-8-20(23-26-10-3-11-27-23)21(12-16)24(30)29-14-18(6-5-17(29)2)15-31-22-9-7-19(25)13-28-22/h3-4,7-13,17-18H,5-6,14-15H2,1-2H3/t17-,18-/m1/s1
  • Key:NPFDWHQSDBWQLH-QZTJIDSGSA-N

See also

References
  1. Hoyer, Daniel; Jacobson, Laura H. (13 November 2017). "Orexin Receptor Antagonists". Current Sleep Medicine Reports. 3 (4): 342–353. doi:10.1007/s40675-017-0099-7. eISSN 2198-6401. hdl:11343/282828. S2CID 80067706.
  2. "Filorexant - AdisInsight".
  3. Hoyer D, Jacobson LH (December 2013). "Orexin in sleep, addiction and more: is the perfect insomnia drug at hand?". Neuropeptides. 47 (6): 477–88. doi:10.1016/j.npep.2013.10.009. PMID 24215799. S2CID 6402764.
  4. Winrow CJ, Gotter AL, Cox CD, et al. (February 2012). "Pharmacological characterization of MK-6096 - a dual orexin receptor antagonist for insomnia". Neuropharmacology. 62 (2): 978–87. doi:10.1016/j.neuropharm.2011.10.003. PMID 22019562. S2CID 35304627.
  5. Peroutka SJ (January 2014). "Clinical trials update. 2013: year in review". Headache. 54 (1): 189–94. doi:10.1111/head.12267. PMID 24400767. S2CID 28141555.
  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. Connor KM, Mahoney E, Jackson S, Hutzelmann J, Zhao X, Jia N, Snyder E, Snavely D, Michelson D, Roth T, Herring WJ (August 2016). "A Phase II Dose-Ranging Study Evaluating the Efficacy and Safety of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Primary Insomnia". Int J Neuropsychopharmacol. 19 (8): pyw022. doi:10.1093/ijnp/pyw022. PMC 5006195. PMID 26979830.
  8. Summers CH, Yaeger JD, Staton CD, Arendt DH, Summers TR (March 2020). "Orexin/hypocretin receptor modulation of anxiolytic and antidepressive responses during social stress and decision-making: Potential for therapy". Brain Res. 1731: 146085. doi:10.1016/j.brainres.2018.12.036. PMC 6591110. PMID 30590027.
  9. Han Y, Yuan K, Zheng Y, Lu L (April 2020). "Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders". Neurosci Bull. 36 (4): 432–448. doi:10.1007/s12264-019-00447-9. PMC 7142186. PMID 31782044.
  10. Connor KM, Ceesay P, Hutzelmann J, Snavely D, Krystal AD, Trivedi MH, Thase M, Lines C, Herring WJ, Michelson D (August 2017). "Phase II Proof-of-Concept Trial of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Major Depressive Disorder". Int J Neuropsychopharmacol. 20 (8): 613–618. doi:10.1093/ijnp/pyx033. PMC 5570043. PMID 28582570.
  11. Michel Alexander Steiner; Christopher J Winrow (11 November 2014). Insomnia and beyond - Exploring the therapeutic potential of orexin receptor antagonists. Frontiers E-books. pp. 3–. ISBN 978-2-88919-330-1.
  12. Joseph Herring W, Ge JY, Jackson S, Assaid C, Connor KM, Michelson D (January 2018). "Orexin Receptor Antagonism in Painful Diabetic Neuropathy: A Phase 2 Trial With Filorexant". Clin J Pain. 34 (1): 37–43. doi:10.1097/AJP.0000000000000503. PMID 28448426. S2CID 23060776.
  13. Chabi, A.; Zhang, Y.; Jackson, S.; Cady, R.; Lines, C.; Herring, W. J.; Connor, K. M.; Michelson, D. (Aug 8, 2014). "Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis". Cephalalgia. 35 (5): 379–88. doi:10.1177/0333102414544979. PMID 25106663. S2CID 20872932.
  14. "Merck Pipeline". Merck. 2015. Retrieved 2015-05-14.


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