Firazorexton

Last updated

Firazorexton
Firazorexton.svg
Clinical data
Other namesTAK-994
Identifiers
  • N-[(2S,3S)-2-[[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl]-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C22H25F3N2O4S
Molar mass 470.51 g·mol−1
3D model (JSmol)
  • CC(C)(C(=O)N1CC[C@@H]([C@@H]1CC2=C(C(=CC=C2)C3=CC(=CC(=C3)F)F)F)NS(=O)(=O)C)O
  • InChI=1S/C22H25F3N2O4S/c1-22(2,29)21(28)27-8-7-18(26-32(3,30)31)19(27)11-13-5-4-6-17(20(13)25)14-9-15(23)12-16(24)10-14/h4-6,9-10,12,18-19,26,29H,7-8,11H2,1-3H3/t18-,19-/m0/s1
  • Key:VOSAWOSMGPKQEQ-OALUTQOASA-N

Firazorexton (INN Tooltip International Nonproprietary Name; development code TAK-994) is an experimental orexin 2 (OX2) receptor agonist first described in a 2019 patent filed by Takeda Pharmaceutical Company. [1] [2]

Firazorexton was studied by Takeda for the treatment of narcolepsy. [3] [4] [5] It is a small-molecule and orally active compound and acts as a highly selective agonist of the orexin receptor 2 (OX2) with >700-fold selectivity over the orexin receptor 1 (OX1). [3] [4] [6] [7] Firazorexton is related to danavorexton (TAK-925). [8]

The compound reached phase 2 clinical trials for narcolepsy. [9] However, clinical development was discontinued in October 2021 for safety reasons. [8] [10] [11] [12] [13] More specifically, it produced severe drug-induced liver injury in phase 2 trials. [14] This hepatotoxicity is unlikely to be related to firazorexton's orexin receptor agonism. [14]

See also

References

  1. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). WHO Drug Information. 34 (1): 93–269. 2020. Proposed INN: List 123
  2. ↑ WOapplication 2019027058,Kajita Y, Mikami S, Miyanohana Y, Koike T, Daini M, Oyabu N, Ogino M, Takeuchi K, Ito Y, Tokunaga N, Sugimoto T, Miyazaki T, Oda T, Hoashi Y, Hattori Y, Imamura K,"Heterocyclic compound and use therof",published 2019-02-07, assigned to Takeda Pharmaceutical Company
  3. 1 2 Ishikawa T, Suzuki M, Kimura H (April 2020). "0141 A Novel, Orally Available Orexin 2 Receptor-Selective Agonist, TAK-994, Shows Wake-Promoting Effects Following Chronic Dosing in an Orexin-Deficient Narcolepsy Mouse Model". Sleep. 43 (Supplement 1): A56. doi: 10.1093/sleep/zsaa056.139 . eISSN   1550-9109. ISSN   0161-8105.
  4. 1 2 Thorpy MJ (January 2020). "Recently Approved and Upcoming Treatments for Narcolepsy". CNS Drugs. 34 (1): 9–27. doi:10.1007/s40263-019-00689-1. PMC   6982634 . PMID   31953791.
  5. ↑ Ishikawa T, Hara H, Kawano A, Tohyama K, Kajita Y, Miyanohana Y, et al. (June 2023). "TAK-994, a Novel Orally Available Brain-Penetrant Orexin 2 Receptor-Selective Agonist, Suppresses Fragmentation of Wakefulness and Cataplexy-Like Episodes in Mouse Models of Narcolepsy". The Journal of Pharmacology and Experimental Therapeutics. 385 (3): 193–204. doi: 10.1124/jpet.122.001449 . PMID   37001988. S2CID   257879743.
  6. ↑ Zhang D, Perrey DA, Decker AM, Langston TL, Mavanji V, Harris DL, et al. (June 2021). "Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists". Journal of Medicinal Chemistry. 64 (12): 8806–8825. doi:10.1021/acs.jmedchem.1c00841. PMC   8994207 . PMID   34101446.
  7. ↑ Pellitteri G, de Biase S, Valente M, Gigli GL (August 2021). "How treatable is narcolepsy with current pharmacotherapy and what does the future hold?". Expert Opinion on Pharmacotherapy. 22 (12): 1517–1520. doi:10.1080/14656566.2021.1915987. PMID   33882765. S2CID   233349300.
  8. 1 2 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. PMID   35043499. S2CID   248119793.
  9. ↑ Clinical trial number NCT04096560 for "A Study of TAK-994 in Adults With Type 1 and Type 2 Narcolepsy" at ClinicalTrials.gov
  10. ↑ "Takeda Provides Update on TAK-994 Clinical Program". Business Wire. 5 October 2021.
  11. ↑ "Takeda pauses TAK-994 clinical studies due to safety glitch". The Pharma Letter. 6 October 2021.
  12. ↑ Jackson M (6 October 2021). "Takeda Halts Phase II Studies For Key R&D Asset TAK-994 In Narcolepsy". Scrip. Informa Pharma Intelligence.
  13. ↑ Tong A (6 October 2021). "Takeda flashes red light on 'breakthrough' narcolepsy drug after PhII trials turned up mysterious safety signal". Endpoints News.
  14. 1 2 Shinozawa T, Miyamoto K, Baker KS, Faber SC, Flores R, Uetrecht J, et al. (April 2025). "TAK-994 mechanistic investigation into drug-induced liver injury". Toxicological Sciences. 204 (2): 143–153. doi:10.1093/toxsci/kfaf003. PMC   11939078 . PMID   39786842.
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