Orexin antagonist

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An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one or both of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders such as insomnia.[1][2]

Examples[]

Marketed[]

  • Daridorexant (nemorexant; Quviviq) – dual OX1 and OX2 antagonist – approved for insomnia in January 2022, formerly under development for sleep apnea syndrome [1] – half-life 6–10 hours
  • Lemborexant (Dayvigo) – dual OX1 and OX2 antagonist – approved for insomnia in December 2019 and released June 1 2020, under development for circadian rhythm sleep disorders, chronic obstructive pulmonary disease, and sleep apnea syndrome – half-life 17–19 hours
  • Suvorexant (Belsomra) – dual OX1 and OX2 antagonist – approved for insomnia in August 2014, under development for delirium – half-life 12 hours

Under development[]

  • Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – selective OX2 antagonist – under development for major depressive disorder, insomnia, and sleep apnea syndrome, up to phase 3 – half-life 2–3 hours [2]
  • Vornorexant (ORN-0829, TS-142) – dual OX1 and OX2 antagonist – under development for insomnia and sleep apnea syndrome, up to phase 2 [3]

Not marketed[]

  • ACT-335827 – selective OX1 antagonist
  • Almorexant (ACT-078573) – dual OX1 and OX2 antagonist – development of the drug was abandoned in January 2011
  • EMPA – selective OX2 antagonist
  • Filorexant (MK-6096) – dual OX1 and OX2 antagonist – development was discontinued in 2015
  • GSK-649868 (SB-649868) – dual OX1 and OX2 antagonist – was in development for potential use in sleep disorders
  • JNJ-10397049 – selective OX2 antagonist
  • RTIOX-276 – selective OX1 antagonist
  • SB-334867 – first non-peptide selective OX1 antagonist – has been shown to produce sedative and anorectic effects in animals[3]
  • SB-408124 – selective OX1 antagonist
  • TCS-OX2-29 – first non-peptide selective OX2 antagonist

Pharmacology[]

Pharmacokinetics[]

The elimination half-lives of clinically used orexin receptor antagonists are 12 hours for suvorexant, about 17 to 19 hours ("effective" half-life) or 55 hours (terminal elimination half-life) for lemborexant, and 6 to 10 hours for daridorexant.[4] The half-life of seltorexant, which is still under development, is only 2 to 3 hours.[4]

References[]

  1. ^ Roecker AJ, Coleman PJ (2008). "Orexin receptor antagonists: medicinal chemistry and therapeutic potential". Curr Top Med Chem. 8 (11): 977–87. doi:10.2174/156802608784936746. PMID 18673167.
  2. ^ Cao M, Guilleminault C (April 2011). "Hypocretin and its emerging role as a target for treatment of sleep disorders". Curr Neurol Neurosci Rep. 11 (2): 227–34. doi:10.1007/s11910-010-0172-9. PMID 21170610.
  3. ^ Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, Upton N, Porter RA, Johns A, Blundell JE (April 2001). "SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats". Eur. J. Neurosci. 13 (7): 1444–52. doi:10.1046/j.0953-816x.2001.01518.x. PMID 11298806.
  4. ^ a b Muehlan C, Vaillant C, Zenklusen I, Kraehenbuehl S, Dingemanse J (November 2020). "Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders". Expert Opin Drug Metab Toxicol. 16 (11): 1063–1078. doi:10.1080/17425255.2020.1817380. PMID 32901578.

External links[]


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