Chemistry:Irdabisant

From HandWiki

Irdabisant (INN, USAN; developmental code name CEP-26401) is a histamine H3 receptor antagonist and inverse agonist which was under development for the treatment of cognition disorders but was never marketed.[1][2][3][4][5][6] It was specifically under development for the treatment of cognitive problems in people with schizophrenia and Alzheimer's disease.[2] The drug is taken orally.[1][7]

It shows high affinity for the histamine H3 receptor (Ki = 2.0 nM) and shows strong selectivity for this receptor over the other histamine receptors and several hundred other targets.[4][5][7] The drug produces wakefulness-promoting effects in both rodents and humans.[5][6] Irdabisant is said to cause "the same energizing and happy feeling as modafinil, but with a more relaxed undertone".[6] In addition however, it dose-dependently disrupts sleep in humans, with side effects including insomnia and headache.[7] The drug can also cause cognitive impairment, perhaps via sleep deprivation, at higher doses.[7] The time to peak levels is 3 to 6 hours and its elimination half-life is 24 to 60 hours.[7]

The chemical synthesis of irdabisant has been described.[4] Analogues of irdabisant have been described.[8][9][10][11]

Irdabisant was under development by Cephalon (since acquired by Teva Pharmaceutical).[1][2] It reached phase 1 clinical trials prior to the discontinuation of its development.[1][2]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 "Irdabisant". 4 November 2017. https://adisinsight.springer.com/drugs/800031631. 
  2. ↑ 2.0 2.1 2.2 2.3 "Several down, a few to go: histamine H3 receptor ligands making the final push towards the market?". Expert Opinion on Investigational Drugs 20 (12): 1629–1648. December 2011. doi:10.1517/13543784.2011.625010. PMID 21992603. 
  3. ↑ "Histamine H3R Antagonists: From Scaffold Hopping to Clinical Candidates". Histamine Receptors. The Receptors. 28. Cham: Springer International Publishing. 2016. pp. 109–155. doi:10.1007/978-3-319-40308-3_5. ISBN 978-3-319-40306-9. 
  4. ↑ 4.0 4.1 4.2 "Discovery and characterization of 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (CEP-26401, irdabisant): a potent, selective histamine H3 receptor inverse agonist". Journal of Medicinal Chemistry 54 (13): 4781–4792. July 2011. doi:10.1021/jm200401v. PMID 21634396. 
  5. ↑ 5.0 5.1 5.2 "CEP-26401 (irdabisant), a potent and selective histamine H₃ receptor antagonist/inverse agonist with cognition-enhancing and wake-promoting activities". The Journal of Pharmacology and Experimental Therapeutics 340 (1): 124–133. January 2012. doi:10.1124/jpet.111.186585. PMID 22001260. 
  6. ↑ 6.0 6.1 6.2 "Central nervous system effects of the histamine-3 receptor antagonist CEP-26401, in comparison with modafinil and donepezil, after a single dose in a cross-over study in healthy volunteers". British Journal of Clinical Pharmacology 85 (5): 970–985. May 2019. doi:10.1111/bcp.13885. PMID 30710391. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "Pharmacokinetics, pharmacodynamics and safety of CEP-26401, a high-affinity histamine-3 receptor antagonist, following single and multiple dosing in healthy subjects". Journal of Psychopharmacology 30 (10): 983–993. October 2016. doi:10.1177/0269881116645301. PMID 27222271. 
  8. ↑ "Synthesis and evaluation of pyridone-phenoxypropyl-R-2-methylpyrrolidine analogues as histamine H3 receptor antagonists". Bioorganic & Medicinal Chemistry Letters 21 (23): 7076–7080. December 2011. doi:10.1016/j.bmcl.2011.09.091. PMID 22014551. 
  9. ↑ "Synthesis of constrained benzocinnolinone analogues of CEP-26401 (irdabisant) as potent, selective histamine H3 receptor inverse agonists". Bioorganic & Medicinal Chemistry Letters 22 (12): 4198–4202. June 2012. doi:10.1016/j.bmcl.2012.04.001. PMID 22617490. 
  10. ↑ "Discovery of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a): histamine H(3) receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity". Bioorganic & Medicinal Chemistry Letters 24 (5): 1303–1306. March 2014. doi:10.1016/j.bmcl.2014.01.061. PMID 24513042. 
  11. ↑ "3,4-Diaza-bicyclo[4.1.0]hept-4-en-2-one phenoxypropylamine analogs of irdabisant (CEP-26401) as potent histamine-3 receptor inverse agonists with robust wake-promoting activity". European Journal of Medicinal Chemistry 95: 349–356. May 2015. doi:10.1016/j.ejmech.2015.03.054. PMID 25827402. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Irdabisant&oldid=4437475"